Cutaneous Reaction Induced by Intramuscular Diclofenac Showing Epidermal Dysmaturation.

Sir,

Diclofenac sodium is a nonsteroidal anti-inflammatory drug (NSAID) commonly used and administered by intramuscular, intravenous, transdermal, and rectal route. In dermatology, it is used for the treatment of actinic keratosis, topically and at a concentration of 3% diclofenac sodium.[1] Several reports of serious complications after diclofenac administration have been reported. We report a case of a man undergoing treatment with diclofenac injections who developed a diffuse cutaneous eruption. His biopsy demonstrated an epidermal dysmaturation, a histopathological pattern typical of adverse chemotherapeutic drug reactions.

A 42-year-old male of Moroccan origin, without any drug allergies or a relevant medical-surgical history, was referred to our Dermatology Unit with a cutaneous rash involving the chest and the genital area. He had received an intramuscular injection of diclofenac a few days ago for low back pain. Physical examination revealed brownish-purple livedoid macules [Figure 1] mainly on the neck, chest, lower extremities, and epidermal detachment in the genital area. The patient reported good general condition, with just discomfort in the genital area. A punch biopsy was taken from the chest for histopathology. The eruption was subsequently resolved with topical corticosteroids (betamethasone) without leaving any residual lesions. Histopathological findings consisted of a focal vacuolization of the basal layer of the epidermis; mitotic figures, and necrotic keratinocytes, as well as incontinentia pigmenti and the presence of melanophages in the superficial dermis [Figure 2].

Figure 1

Brownish macules on neck and chest

Figure 2

Epidermal dysmaturation showing focal vacuolization of the basal layer of the epidermis; mitotic figures, and apoptotic cells, as well as incontinentia pigmenti and the presence of melanophages in the superficial dermis (Hematoxylin and eosin). HE10x the picture top left, HE20x top right and tha photos below are HE40x

Horn described “keratinocyte dysmaturation” as keratinocyte dysplasia changes secondary to chemotherapy or transplant recipients with acute GvHD.[2] Epidermal dysmaturation is a histological finding referring to changes in the epidermis and inflammation, such as irregular large nuclei, loss of polarity, apoptosis, mitotic figures, and disruption of keratinocyte maturation after receiving chemotherapy, transplantation, or development of graft versus host disease.[3] This is a typical complication of treatment with taxanes and pegylated liposomal doxorubicin, although cases with other cytotoxic and immunosupresive drugs such as cyclophosphamide, busulfan, cyclosporine, etopside, thiotepa, and methotrexate have been described.[4] Recently, a case of epidermal dysmaturation has been described in a patient under treatment with regorafenib, a multi-kinase inhibitor drug, expanding the histological variety of adverse effects in this type of drugs.[5]

Diclofenac sodium is a derivative of phenylacetic acid and belongs to the group of NSAIDs. This anti-inflammatory drug is preferred in medical departments to control pain, as used in our patient to relieve low back pain. Intramuscular injection of diclofenac is not without complications, both local and systemic. Systemic adverse effects such as asthmatic attack, urticaria, ischemic stroke, Kounis syndrome, and anaphylaxis may appear after the administration of diclofenac sodium.[6] In addition, local side effects such as Nicolau syndrome[7] and necrotizing fasciitis[8] can be a serious complication of intramuscular diclofenac.

The clinic of the cutaneous chemotherapy reactions is very wide, ranging from stomatitis, photosensitivity and hypersensitivity reactions. The cutaneous clinic that our patient experienced is very similar to that produced by epidermal dysmaturation due to chemotherapy, with hyperpigmented patches in the trunk and the genital involvement.[9]

The precise pathogenesis leading to dysmaturation is unclear but probably results from the direct cytotoxic effects of the chemotherapeutic agent on keratinocytes[10] affecting the DNA. However, multi-kinase inhibitor drugs do no target DNA directly, making it difficult to explain the causality between regorafenib and epidermal dysmaturation.[5] Diclofenac works by inhibiting the synthesis of prostaglandins through the competitive and reversible inhibition of cyclooxygenase activity, an enzyme that converts arachidonic acid into prostaglandins. NSAID cause depression of cellular function and enhancement of tumor necrosis factor, supporting the cytotoxic effect of the drug.[11] However, many questions remain to be answered in these types of drug skin reactions.

In summary, this report describes a case of epidermal dysmaturation, a rare side effect caused by diclofenac injection.

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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.

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Conflicts of interest

There are no conflicts of interest.