sirolimus-induced leukocytoclastic vasculitis: the second case reported

American Journal of Transplantation 2004; 4: 1549–1551Blackwell Munksgaard

Copyright C© Blackwell Munksgaard 2004

doi: 10.1111/j.1600-6143.2004.00513.x

Letter to the Editor

Sirolimus-Induced Leukocytoclastic Vasculitis:The Second Case Reported

To the Editor:

Sirolimus (Rapamune®) is an immunosuppressive agentused for the prevention of organ rejection after transplan-tation. In general, adverse effects relating to the adminis-tration of sirolimus are dependent on dose/concentration,and include leukopenia, thrombocytopenia, anemia, hyper-cholesterolemia, diarrhea, and hypertriglyceridemia (1). Re-cently, leukocytoclastic vasculitis has been described in as-sociation with sirolimus use (2). In this letter, we presentthe case of a 36-year-old white female who had undergonesimultaneous kidney–pancreas transplantation in October2002 for end-stage renal disease secondary to long-stagediabetes mellitus type 1 and developed leukocytoclasticskin vasculitis after exposure to sirolimus. Prior to trans-plantation, she had no previous episodes of vasculitis, se-vere ulcers or gangrene.

Initial immunosuppressive regimen was a combination ofprednisone, tacrolimus, and sirolimus (2 mg q.d.); she re-ceived two doses of daclizumab. For 2 weeks after trans-plantation, hemodialysis was required due to acute tubu-lar necrosis; the patient also developed renal acute rejec-tion grade IIA (Banff 1997), requiring pulse therapy withmethylprednisolone. Acute pyelonephritis caused by mul-tiresistant Klebsiella pneumoniae was later treated witha 14-day course of imipenem cilastatin. She was dis-charged 36 days after surgery, with normal renal and pan-creatic functions, and using the same immunosuppressiveregimen.

Three months after transplantation, the patient reportedred, painful papules on her hands and fingers, but with-out a fever. These lesions progressively increased in size,and on May 2003 she was hospitalized to investigate bi-lateral ulcerative necrotic lesions on her hands, some ofthem with an erythematous halo (Figure 1). Skin biopsyrevealed leukocytoclastic vasculitis (Figure 2). Gram stainwas negative for microorganisms, as well as mycologicalexamination.

Sirolimus was considered as the probable causativeagent of cutaneous leukocytoclastic vasculitis, and it wasswitched to mycophenolate mofetil in June 2003. Con-current medication was tacrolimus, prednisone, acetyl-salicylic acid, co-trimoxazole, cephalexin, acetaminophen,

enalapril, and omeprazole. Sirolimus concentration was notavailable at that time; previous serum through concen-trations were 8.7 ng/mL (October 2002), and 5.8 ng/mL(December 2002). After sirolimus discontinuation, the vas-culitis resolved within weeks, and a new surgical pro-cedure was performed to remove the necrotic tissue.Figure 1 shows the patient’s hand 4 months after sirolimusdiscontinuation.

Leukocytoclastic vasculitis is a histopathologic processmanifested by necrotizing vasculitis, with segmental areasof transmural infiltration and disruption of the vessel archi-tecture by neutrophils with fibrinoid necrosis (3). Althoughmost cases of cutaneous vasculitis are idiopathic, severalconditions have been linked to leukocytoclastic vasculi-tis, including infection, inflammatory diseases, malignancy,and drug intake (2,3).

Leukocytoclastic vasculitis was previously reported in as-sociation with sirolimus, in a patient who had undergonelung transplantation. The diagnosis of sirolimus-inducedvasculitis was based on the temporal relationship betweendrug therapy and the biopsy-proven vascular inflammation,resolution of the inflammation upon discontinuation of drugtherapy, and similar occurrences with reinitiating sirolimus(2). Similarly to that case report, this patient was also tak-ing co-trimoxazole; this medication was maintained un-changed throughout the course of her cutaneous eruptionand its subsequent resolution. Cephalexin, which couldalso be associated with cutaneous vasculitis (4), was ini-tiated after the lesions had already begun. To conclude,we reinforce a previous report (2) that sirolimus should beconsidered among the medications responsible for leuko-cytoclastic vasculitis.

Alessandro C. Pasqualottoa

Patrcia D. Biancob

Teresa C. T. Sukiennika

Roque Furianc

Valter D. Garciab

Departments of aInfection ControlbNephrology, and cPathology

Santa Casa Complexo HospitalarPorto Alegre

Brazil

1549

Pasqualotto et al.

Figure 1: 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).

Figure 2: 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).

1550 American Journal of Transplantation 2004; 4: 1549–1551

Sirolimus-Induced Leukocytoclastic Vasculitis

References

1. Rapamune (sirolimus) [package insert]. Philadelphia: Wyeth Labo-ratories, 2001.

2. Hardinger KL, Cornelius LA, Trulock EP 3rd, Brennan DC.Sirolimus-induced leukocytoclastic vasculitis. Transplantation2002; 74: 739.

3. Fiorentino DF. Cutaneous vasculitis. J Am Acad Dermatol 2003;48: 311.

4. Calabrese LH, Duna GF. Drug-induced vasculitis. Curr OpinRheumatol 1996; 8: 34.

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