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Saudi Journal of Kidney Diseases and Transplantation
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CASE REPORT  
Year : 2020  |  Volume : 31  |  Issue : 5  |  Page : 1106-1109
Leukocytoclastic Vasculitis Associated with Bortezomib Therapy


Department of Nephrology, Government Stanley Medical College, Chennai, Tamil Nadu, India

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Date of Web Publication21-Nov-2020
 

   Abstract 


A 28-year-old male, 10 years post live-related renal transplant with stable graft function of 1.4 mg/dL, presented with complaints of loss of appetite and vomiting for three days. On evaluation, he was found to have significant graft dysfunction with a creatinine of 10.3 mg/dL. He was initiated on hemodialysis in view of uremic gastrointestinal symptoms. Graft biopsy done revealed acute cell-mediated rejection BANFF IIB and diffuse C4d-positive antibody-mediated rejection. He was treated with intravenous methylprednisolone, therapeutic plasma exchange, and intravenous immunoglobulin therapy, following which his graft function improved gradually. He received multiple injections of bortezomib as a part of anti-rejection treatment protocol and developed peripheral neuropathy, leukocytoclastic vasculitis, and varicellosis. This case report is to highlight the unusual phenomenon of leukocytoclastic vasculitis in a post renal transplant setting secondary to bortezomib therapy.

How to cite this article:
Yashwanth TR, Vairakkani R, Srinivasaprasad ND, Sujith S, Thirumalvalavan K, Fernando ME. Leukocytoclastic Vasculitis Associated with Bortezomib Therapy. Saudi J Kidney Dis Transpl 2020;31:1106-9

How to cite this URL:
Yashwanth TR, Vairakkani R, Srinivasaprasad ND, Sujith S, Thirumalvalavan K, Fernando ME. Leukocytoclastic Vasculitis Associated with Bortezomib Therapy. Saudi J Kidney Dis Transpl [serial online] 2020 [cited 2020 Dec 1];31:1106-9. Available from: https://www.sjkdt.org/text.asp?2020/31/5/1106/301178



   Introduction Top


Cutaneous small-vessel vasculitis (CSVV) is a single-organ, skin-isolated, small-vessel vasculitis associated with leukocytoclasia, without systemic vasculitis or glomerulonephritis. Leukocytoclastic vasculitis (LCV) is a histopathologic term in which the inflammatory infiltrate is composed of neutrophils which undergo death and break down, a process named leukocytoclasia, releasing nuclear debris. This can present either as a palpable purpura or erythematous maculo-papular rash. We report a 10-year postrenal transplant recipient who had significant graft dysfunction secondary to acute cell-mediated BANFF IIB and C4d-positive antibody-mediated rejection and developed leukocytoclastic vasculitis following bortezomib therapy as a part of anti-rejection treatment protocol.


   Case Report Top


Informed consent was obtained from the patient before publishing the case.

A 28-year-old male, 10 years post live related renal transplant, with mother as donor presented with complaints of loss of appetite and vomiting for three days. He had been doing well with a nadir creatinine of 1.4 mg/dL with no significant admissions in the past. He was on cyclosporine 100 mg/day, azathioprine 75 mg/day, and prednisolone 5 mg/day.

Evaluation showed severe graft dysfunction with a creatinine of 10.3 mg/dL and was initiated on hemodialysis in view of uremic gastrointestinal symptoms. Graft biopsy revealed diffuse C4d-positive antibody-mediated rejection with acute cell-mediated rejection BANFF II B with no significant interstitial fibrosis or tubular atrophy. Presence of donor-specific antibodies could not be ascertained due to logistic reasons.

He denied non-compliance to therapy and was treated with three doses of intravenous pulse methylprednisolone (2 g in total) on consecutive days and six sessions of therapeutic plasma exchange (TPE) on alternate days accompanied by 100 mg/kg/dose of intravenous immunoglobulin (IVIG) after each session. The last session of TPE was followed by 500 mg/kg of IVIG. Cyclosporine and azathioprine were stopped, and he was initiated on tacrolimus and mycophenolate mofetil (MMF)-based regimen. Oral prednisolone dose was increased to 20 mg/day. CMV infection being a remote possibility, CMV PCR was done ruling out the same.

His graft function improved to attain a stable creatinine of 2.0 mg/dL. The first dose of injection bortezomib 1.3 mg/m2 was given subcutaneously, and he was discharged. A week later, he presented with pain and paresthesia over both hands and forearm. The possibility of bortezomib-induced peripheral neuropathy was considered, and he was started on tablet amitriptyline 100 mg once daily. As recommended by the United States, Food and Drug Administration agency, our patient received a modified second dose of bortezomib at 1 mg/m2 in view of prior pain and paraesthesia.[1]

Four days later, he developed multiple erythematous, purpuric lesions distributed symmetrically over both hands and forearm [Figure 1]. The differentials considered were drug-induced vasculitis (DIV), urticarial rash, and hypersensitivity reaction. Skin biopsy was done. Light microscopy revealed scattered lymphocytic infiltration in the dermis and thin-walled small vessels lined by flattened endothelial cells which were infiltrated by neutrophils and their nuclear debris in the absence of fibrinoid necrosis, favoring a diagnosis of leukocytoclastic vasculitis [Figure 2] and [Figure 3]. Immunofluorescence staining for antibodies and complements was negative.
Figure 1: Multiple erythematous, purpuric rashes symmetrically distributed over both hands.

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Figure 2: Thin-walled small vessels lined by flattened endothelial cells, infiltrated by neutrophils and their nuclear debris ×40.

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Figure 3: Squamous epithelium with scattered lymphocytic infiltration in the dermis and small-vessel vasculitis with neutrophilic infiltration ×10.

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He was previously on 4.5 mg/day of tacrolimus, 1 g/day of MMF, and 20 mg/day of prednisolone and hence, was only observed for further progression of symptoms. The rash resolved spontaneously over a period of two weeks. As the development of rash is not a contraindication for bortezomib therapy, he received the third dose of bortezomib at 0.7 mg/m2,[1] to only cause worsening of peripheral neuropathy and recurrence of the rash. Hence, further doses of bortezomib were withheld. About a week later, he developed varicellosis which was treated with intravenous acyclovir therapy. The patient is currently on follow-up with us on an outpatient basis and is doing well with a creatinine of 2.2 mg/dL.


   Discussion Top


CSVV is defined as a single-organ, skin-isolated, small-vessel vasculitis associated with leukocytoclasia, without systemic vasculitis or glomerulonephritis.[1]

LCV is a histopathologic term that defines vasculitis of the small vessels in which the inflammatory infiltrate is composed of neutrophils. After degranulation, neutrophils undergo death and break down, a process named leukocytoclasia, releasing nuclear debris.[2]

In early lesions, a neutrophilic infiltrate predominates with a perivascular or diffuse dermal distribution followed by mixed infiltrates with leukocytoclasia, along with endothelial changes, fibrinoid necrosis, and extravasation of erythrocytes. CSVV presents as either a palpable purpura or erythematous maculopapular rash, with the latter being more common.[2]

Many medications can cause CSVV, but penicillins, cephalosporins, sulfonamides, phenytoin, and allopurinol have been most often implicated. These drugs may act as haptens to stimulate an immune response.[3]

Rashes have been reported in 8%–18% of patients in clinical trials of bortezomib. Cutaneous manifestations commonly include vasculitic acneiform rash, folliculitis-like rash, Sweet's syndrome, and small-vessel vasculitis.[4] Clinical features of DIV can be similar to those of the idiopathic vasculitides. Presentations range from self-limiting illness restricted to the skin to multi-organ involvement requiring glucocorticoids.[4]

The causal association of bortezomib with LCV is emphasized by the pattern of resolving and recurring rash following withdrawal and re-exposure to the drug, while other medications remain unchanged. There are no pathognomonic features to DIV that help distinguish it from other vasculitides. It is usually a diagnosis of exclusion and citing one particular causal agent requires careful attention to all medications being prescribed to the patient.

The exact mechanism behind bortezomib-induced vascular inflammation is unclear. It has been shown that bortezomib triggers transcription of proteasome subunits and chaperones of the heat shock protein family, inducing a stress response. This leads to overproduction of pro-inflammatory cytokines including interleukin-6 and tumor necrosis factor alpha, which may play a role in bortezomib-induced CLV.[4]

Agterof and Biesma and Garcia-Navarro et al reported the occurrence of CSVV in patients with multiple myeloma who received borte-zomib therapy.[5],[6] In addition, a retrospective analysis by Gerecitano et al, of data from 140 patients with non-Hodgkin lymphoma who received single-agent bortezomib, identified 26 patients who developed erythematous maculopapular rash. Six of these patients had underwent skin biopsy, all of which revealed small-vessel vasculitis.[7]

The management of DIV is tailored to the presentation and the patient's response to withdrawal of the suspected causative agent. If symptoms do not improve with withdrawal of the suspected agent, it may be prudent to systematically eliminate other agents one at a time.

The experience with bortezomib in lymphoma patients suggests that treatment may safely proceed without dose adjustment in patients who develop an isolated cutaneous vasculitis in response to bortezomib therapy. Steroids may be added in patients where treatment options are limited or when the patient appears to be responding to the therapy.[8]


   Declaration of Patient Consent Top


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

Conflict of interest: None declared.



 
   References Top

1.
Velcade® label [U.S. package insert]. Available from: http://www.fda.gov/cder/ approval/index.htm. [Last accessed on January 10, 2020].  Back to cited text no. 1
    
2.
Jennette JC, Falk RJ, Bacon PA, et al. 2012 revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides. Arthritis Rheum 2013;65:1-1.  Back to cited text no. 2
    
3.
Mullick FG, McAllister HA Jr., Wagner BM, Fenoglio JJ Jr. Drug related vasculitis. Clinicopathologic correlations in 30 patients. Hum Pathol 1979;10:313-25.  Back to cited text no. 3
    
4.
Min CK, Lee S, Kim YJ, et al. Cutaneous leucoclastic vasculitis (LV) following bortezomib therapy in a myeloma patient; association with pro-inflammatory cytokines. Eur J Haematol 2006;76:265-8.  Back to cited text no. 4
    
5.
Agterof MJ, Biesma DH. Images in clinical Medicine. Bortezomib-induced skin lesions. N Engl J Med 2005;352:2534.  Back to cited text no. 5
    
6.
Garcia-Navarro X, Puig L, Fernández-Figueras MT, Dalmau J, Roe E, Alomar A. Bortezomib-associated cutaneous vasculitis. Br J Dermatol 2007;157:799-801.  Back to cited text no. 6
    
7.
Gerecitano J, Goy A, Wright J, et al. Drug-induced cutaneous vasculitis in patients with non-Hodgkin lymphoma treated with the novel proteasome inhibitor bortezomib: A possible surrogate marker of response? Br J Haematol 2006;134:391-8.  Back to cited text no. 7
    
8.
O’Connor OA, Wright J, Moskowitz C, et al. Phase II clinical experience with the novel proteasome inhibitor bortezomib in patients with indolent non-Hodgkin's lymphoma and mantle cell lymphoma. J Clin Oncol 2005;23: 676-84.  Back to cited text no. 8
    

Top
Correspondence Address:
Raveendran Vairakkani
Department of Nephrology, Government Stanley Medical College, Chennai, Tamil Nadu
India
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DOI: 10.4103/1319-2442.301178

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    Figures

  [Figure 1], [Figure 2], [Figure 3]



 

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