Gemcitabine induced vasculitis: an increasing trend

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Dear Editor, Gemcitabine is a pyrimidine nucleoside and an analog of cytarabine which replaces cytidine during DNA replication. It has been used in various solid tumors like lung, pancreas, bladder, colon, ovarian, and breast cancer [1]. Its most common side-effect is myelosuppression, but flu‐like symptoms, oedema, cutaneous rash, pulmonary toxicity, deep venous thrombosis, and hemolytic uraemic syndrome have also been described. Few cases of cutaneous and vascular side-effects of gemcitabine therapy have been reported [2,3]. Here we discuss a case of vasculitis followed by gemcitabine treatment. A 67-year-old female was diagnosed as a case of advanced non-small cell lung cancer six months ago and was started on gemcitabine cycles every three weeks. After three days of the fourth cycle of chemotherapy, she presented with rashes over both legs associated with swelling. It was not associated with itching, oozing, scaling or ulceration. General physical and systemic examinations were within normal limits. Dermatological examination revealed erythematous palpable purpura over bilateral legs extending up to the upper thigh (Fig. 1a, b). The rash was nonblanchable by diascopy (Fig. 1c). Her complete blood count, liver and renal function tests, and urinalysis were found to be in normal range. The immunological test consisting of antinuclear antibody, antineutrophilic cytoplasmic antibody, perinuclear antineutrophil cytoplasmic antibody, and extractable nuclear antibody profile were negative. The chest radiography showed left sided pleural effusion and ultrasound of the abdomen revealed moderate ascites and was interpreted secondary to underlying carcinoma. Serology for HIV I and II, Hepatitis B and C were negative. The colour doppler ultrasound of bilateral lower limbs were also normal. Histopathology from skin biopsy revealed an unremarkable epidermis with an underlying dermis showing disease activity predominantly around the vessels. The endothelial cells were plump with perivascular infiltration by neutrophils with karyorrhectic debris. Extravasation of red blood cells was noted in the perivascular areas (Fig. 2a–c). However, no evidence of fibrinoid necrosis of the vessel wall was seen. Based on these findings, the patient was diagnosed as a cutaneous small vessel leukocytoclastic vasculitis. The Naranjo score for gemcitabine as a putative agent for vasculitis was 7 (probable). The chemotherapy regimen was discontinued and the patient was managed with a short course of oral prednisolone 40 mg/day tapered over 2 weeks with topical emollients following which there was complete resolution of purpura. The oncophysician was conveyed to switch to a suitable alternative of gemcitabine. Since then the patient has not had recurrence of vasculitis. Leukocytoclastic vasculitis due to underlying malignancy may present as a paraneoplastic phenomenon. In our patient, the skin lesions did not relapse when the prednislone was stopped, and it did not recur even with the progression of carcinoma.Figure 1: a, b: Dermatological examination shows purpura over both legs; c: the lesions were nonblanchable on diascopy.Figure 2: a: Histopathology from skin biopsy revealed an unremarkable epidermis; the dermis shows perivascular infiltrates. 2b and c: On higher magnification, the endothelial cells were plump with perivascular infiltration by neutrophils with karyorrhectic debris with extravasation of red blood cells. (×10, 40 H&E).Cutaneous toxicity associated with gemcitabine has been adequately reported in literature. It presents as a nonspecific maculopapular rash, erysipeloid skin lesions, scleroderma-like changes, linear immunoglobulin A bullous dermatosis, peripheral edema, anasarca, pseudo-cellulitis, radiation-recall dermatitis and pseudolymphomas [1]. The vascular adverse effects of gemcitabine that have been reported are- venous thromboembolism, splenic venous thrombosis veno–occlusive disease of liver, myocardial infarction, stroke, Raynaud’s phenomenon, digital ischemia, exacerbation of peripheral vascular disease, hemolytic–uremic syndrome and thrombotic thrombocytopenic purpura [2]. Vasculitis due to gemcitabine has been rarely observed and less than 10 cases have been reported till date worldwide [3,4]. Vascular toxicity due to gemcitabine is a well-recognized secondary effect and is due to interference in coagulation and immune pathways. The exact mechanism by which gemcitabine leads to vasculitis is unknown but it has been considered an immune reaction to a precipitating antigen of the gemcitabine. In conclusion, gemcitabine as a chemotherapeutic agent is increasingly being used and the recent literature suggests an upward trend in its vascular adverse effects. Vasculitis although rare, occurs due to gemcitabine. Acknowledgments Declaration of patient consent: The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient has given the consent for images and other clinical information to be reported in the journal. The patient understands that names and initials will not be published and due efforts will be made to conceal patient identity, but anonymity cannot be guaranteed. Patient consent: Taken. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.

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