Sirolimus-Induced Leukocytoclastic Vasculitis: The Second Case Reported

Abstract

To the Editor: Sirolimus (Rapamune®) is an immunosuppressive agent used for the prevention of organ rejection after transplantation. In general, adverse effects relating to the administration of sirolimus are dependent on dose/concentration, and include leukopenia, thrombocytopenia, anemia, hypercholesterolemia, diarrhea, and hypertriglyceridemia (1). Recently, leukocytoclastic vasculitis has been described in association with sirolimus use (2). In this letter, we present the case of a 36-year-old white female who had undergone simultaneous kidney–pancreas transplantation in October 2002 for end-stage renal disease secondary to long-stage diabetes mellitus type 1 and developed leukocytoclastic skin vasculitis after exposure to sirolimus. Prior to transplantation, she had no previous episodes of vasculitis, severe ulcers or gangrene. Initial immunosuppressive regimen was a combination of prednisone, tacrolimus, and sirolimus (2 mg q.d.); she received two doses of daclizumab. For 2 weeks after transplantation, hemodialysis was required due to acute tubular necrosis; the patient also developed renal acute rejection grade IIA (Banff 1997), requiring pulse therapy with methylprednisolone. Acute pyelonephritis caused by multiresistant Klebsiella pneumoniae was later treated with a 14-day course of imipenem cilastatin. She was discharged 36 days after surgery, with normal renal and pancreatic functions, and using the same immunosuppressive regimen. Three months after transplantation, the patient reported red, painful papules on her hands and fingers, but without a fever. These lesions progressively increased in size, and on May 2003 she was hospitalized to investigate bilateral ulcerative necrotic lesions on her hands, some of them with an erythematous halo (Figure 1). Skin biopsy revealed leukocytoclastic vasculitis (Figure 2). Gram stain was negative for microorganisms, as well as mycological examination. Sirolimus-induced leukocytoclastic vasculitis. The first two pictures were taken while the patient was using sirolimus (above). Below, the same patient 3 weeks (on the left) and 4 months after drug suspension (on the right). Anatomopathological studies of skin biopsy. On the left, there is a superficial ulcer with an exsudate composed of fibrin, neutrophils and lymphocytes. On the right, neutrophils infiltrating small blood vessel walls, associated with neutrophil nuclear fragments (leukocytoclastic vasculitis). Sirolimus was considered as the probable causative agent of cutaneous leukocytoclastic vasculitis, and it was switched to mycophenolate mofetil in June 2003. Concurrent medication was tacrolimus, prednisone, acetylsalicylic acid, co-trimoxazole, cephalexin, acetaminophen, enalapril, and omeprazole. Sirolimus concentration was not available at that time; previous serum through concentrations were 8.7 ng/mL (October 2002), and 5.8 ng/mL (December 2002). After sirolimus discontinuation, the vasculitis resolved within weeks, and a new surgical procedure was performed to remove the necrotic tissue. Figure 1 shows the patient's hand 4 months after sirolimus discontinuation. Leukocytoclastic vasculitis is a histopathologic process manifested by necrotizing vasculitis, with segmental areas of transmural infiltration and disruption of the vessel architecture by neutrophils with fibrinoid necrosis (3). Although most cases of cutaneous vasculitis are idiopathic, several conditions have been linked to leukocytoclastic vasculitis, including infection, inflammatory diseases, malignancy, and drug intake (2, 3). Leukocytoclastic vasculitis was previously reported in association with sirolimus, in a patient who had undergone lung transplantation. The diagnosis of sirolimus-induced vasculitis was based on the temporal relationship between drug therapy and the biopsy-proven vascular inflammation, resolution of the inflammation upon discontinuation of drug therapy, and similar occurrences with reinitiating sirolimus (2). Similarly to that case report, this patient was also taking co-trimoxazole; this medication was maintained unchanged throughout the course of her cutaneous eruption and its subsequent resolution. Cephalexin, which could also be associated with cutaneous vasculitis (4), was initiated after the lesions had already begun. To conclude, we reinforce a previous report (2) that sirolimus should be considered among the medications responsible for leukocytoclastic vasculitis.