Introduction

Leuprolide (Lupron) is a gonadotropin-releasing hormone (GnRH) agonist which acts on pituitary GnRH receptors down-regulating the secretion of Luteinizing hormone and Follicle stimulating hormone [1]. Leuprolide is used as a hormonal antagonist in the treatment of advanced prostatic cancer, and as hormonal therapy in the treatment of endometriosis [2]. Ever since its FDA approval in 1985, many adverse reactions have been reported in association with leuprolide ranging from local skin irritation to severe anaphylactoid reactions [3]. In this case report, we present a patient who developed hypersensitivity vasculitis (serum sickness) after receiving leuprolide for his newly diagnosed prostate cancer. Hypersensitivity vasculitis has never been reported as a side-effect of leuprolide. Our case is

the first case of hypersensitivity vasculitis associated with leuprolide.

Case report

A 67-year-old male from Connecticut with prostate cancer and hypertension was admitted to our hospi-tal due to his spreading rash and high grade fever. The rash started in his right leg as a small maculopapu-lar rash five weeks previously and was diagnosed as erythema chronicum migrans due to Lymes disease. Hence, he was treated with doxycycline for 21 days with the rash disappearing, only to reappear. Later a dermatologist diagnosed the rash as eczema and prednisone was prescribed a week before admis-sion here. Five days prior to admission while being

Cutaneous and Ocular Toxicology, 2010; 29(3): 224–227

C A S E R E P O R T

Hypersensitivity vasculitis associated with leuprolide (Lupron)

Joseph Gnanaraj1 and Muhammad Wasif Saif2

1Internal Medicine Residency Program, Assistant Program Director, Griffin Hospital, Derby, CT, Affiliated to Yale University School of Medicine, New Haven, and 2GI Cancers Program, Yale Cancer Center, Yale University School of Medicine, New Haven, CT, USA

AbstractLeuprolide (Lupron) is a synthetic analog of naturally occurring gonadotropin-releasing hormone (GnRH). Leuprolide is used as a hormonal antagonist in the treatment of advanced prostatic cancer, and as hormonal therapy in the treatment of endometriosis. Off-label, it is also used in premenopausal or perimenopausal women with hormone-responsive breast cancer for the purpose of ovarian ablation. Ever since its FDA approval in 1985, many adverse reactions have been reported in association with leuprolide ranging from local skin irritation to severe anaphylactoid reactions. In this case report, we present a case of hypersensitivity vasculitis (serum sickness) in a patient who received leuprolide for his prostate cancer. Serum sickness has never been reported as a side-effect of leuprolide. Our case is the first case of serum sickness associated with leuprolide. We emphasize that physicians using leuprolide should be wary of signs and symptoms of hypersensitivity vasculitis or serum sickness.

Keywords: Hypersensitivity vasculitis; serum sickness; leuprolide; GnRH analogues; prostate cancer

Address for Correspondence: M. Wasif Saif, MD, MBBS, Associate Professor, Co-Director, GI Cancers Program, Yale Cancer Center, Yale University School of Medicine, New Haven, CT, USA. Tel.: +1 203 737 1569. Fax: +1 203 785 3788. E-mail: wasif.saif@yale.edu

(Received 23 March 2010; revised 15 April 2010; accepted 19 April 2010)

ISSN 1556-9527 print/ISSN 1556-9535 online © 2010 Informa UK LtdDOI: 10.3109/15569527.2010.487505 http://www.informahealthcare.com/cot

Cutaneous and Ocular Toxicology2010

224227

1556-95271556-9535© 2010 Informa UK Ltd10.3109/15569527.2010.487505

23 March 201019 April 201015 April 2010

COT

487505

Cut

aneo

us a

nd O

cula

r T

oxic

olog

y D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y C

DL

-UC

San

ta C

ruz

on 1

2/04

/14

For

pers

onal

use

onl

y.

Hypersensitivity vasculitis associated with leuprolide 225

on prednisone taper, the patient found his rash was spreading while on a trip to North Carolina. He also developed high grade fever of 102°F with chills next day. Fever was associated with headache with no nau-sea, vomiting or cardio respiratory symptoms. Diffuse pruritis developed as well. Examination revealed a febrile patient with a diffuse maculopapular rash (Figures 1and 2).

He revealed that he was diagnosed with prostate cancer and was started on bicalutamide. Later in two months, leuprolide was added due to poor response of the tumor and he received his second dose of leu-prolide 10 days prior to admission here. On admission he was taking hydrochlorothiazide, atenolol, tapering dose of prednisone and simvastatin along with bical-utamide. The only new drug which the patient received was leuprolide.

On admission the white cell count was 7000/cubic millimeter with granulocytes 0f 87% and eosionphils of

5.8%. The hemoglobin was 13.8 gm/dl and platelet count was 210,000/microliter. Liver function tests and renal function tests were normal. Urine analysis was normal except for trace hemoglobin. Lyme titer which was car-ried out five weeks previously was reportedly negative.

The patient was started empirically on doxycycline for probable Rocky Mountain spotted fever or dis-seminated Lyme’s disease. Prednisone was stopped on the day of admission. Within 48 hours, the patient developed diffuse joint pain with joint swelling (Figure 3) involving both larger and smaller joints of the upper and lower extremities. Serologies for Lyme’s disease, ehrlichiosis and Rocky Mountain spotted fever were negative. The patient was diagnosed with

Figure 3. Arthritis of knee joints and the maculopapular rash from hypersensitivity vasculitis.

Figure 2. Maculopapular rash in the posterior aspect of the trunk from hypersensitivity vasculitis.

Figure 4. Skin biopsy specimen stained with hematoxylin and eosin staining reveals perivascular lymphocytic infiltrate.

Figure 1. Diffuse maculopapular rash as a consequence of hypersensitivity vasculitis.

Cut

aneo

us a

nd O

cula

r T

oxic

olog

y D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y C

DL

-UC

San

ta C

ruz

on 1

2/04

/14

For

pers

onal

use

onl

y.

226 J. Gnanaraj and M. Wasif Saif

hypersensitivity vasculitis based on the constellation of clinical findings of diffuse rash, fever, arthralgia and arthritis. Leuprolide was attributed as the cause because of the temporal pattern of the onset of the ill-ness after the second dose of leuprolide. On Naranjo’s scale, the patient scored 5, implying a probable adverse reaction to leuprolide. Skin biopsy of the lesion revealed perivascular lymphocytic infiltrate (Figure 4). The patient’s symptoms including rash and arthritis improved with steroids.

Discussion

Serum sickness or hypersensitivity vasculitis is an example of the Type III, or immune complex–mediated, hypersensitivity disease. The molecular size, charge, structure, amount, and valence of the antigen involved influence the type of immune complexes formed [4]. After the initial exposure to a foreign antigen in the absence of a pre-existing antibody, serum sickness can develop within 1–2 weeks. Upon subsequent exposure, however, serum sickness develops sooner. The disease appears as the antibody formation begins, and the pathogenesis of serum sickness is related to protracted interaction between antigen and antibody in the circulation, with antigen-antibody complex formation in an environment of antigen excess. The resulting inflam-matory reaction causes the signs and symptoms of hypersensitivity vasculitis or serum sickness. Serum sickness-like reaction presents with similar signs and symptoms but are believed to be caused by different mechanism.

Hypersensitivity vasculitis develops 1–3 weeks after administration of the causative agent (in

many cases a medication) is initiated but can occur within 12–36 hours in individuals who have been previously sensitized through an antecedent expo-sure. Symptoms commonly associated with serum sickness include fever/malaise (100%), cutaneous eruptions (93%), arthralgia (77%), gastrointestinal complaints (67%), headaches (57%), myalgias (37%) and lymphadenopathy (17%) [8]. The rash associated with serum sickness is urticarial and/or serpiginous that starts in the anterior lower trunk, groin, periumbilical, or axillary regions, and spreads to involve the back, upper trunk, and extremities. Other skin manifestations may include palpable purpura, morbilliform rashes, papules, or maculo-papular lesions. Arthritis (10–50%) occurs usually in the metacarpophalangeal and knee joints and is usually symmetrical. The most common causes of serum sickness include anti-toxins, anti-venins, hormones from other species, streptokinase, anti-bacterials, etc. [5–7].

Diagnosis is usually made on the clinical grounds and could be supported with the following labora-tory findings. Complete blood count may reveal neu-tropenia, mild thrombocytopenia or eosinophilia. C-reactive protein, erythrocyte sedimentation rate is elevated in active serum sickness. Skin biopsy might reveal mild perivascular infiltrates consisting of lym-phocytes and histiocytes, in the absence of vessel necrosis [9].

The management of these reactions primarily involves discontinuation of possible culprit agents. Typically, fever and arthralgias resolve and new skin lesions stop forming within 48 hours of this intervention. Antihistamines may be administered for symptomatic relief of pruritus. Non-steroidal anti-inflammatory agents and analgesics may be given for symptomatic treatment of low-grade fever and arthralgias. For patients with higher fever (e.g., temperature > 101.0°F), more severe arthritis and arthralgias, or extensive rashes, a short course of glu-cocorticoids can be used and tapered within a week [10]. Once serum sickness develops, the responsible drug should be avoided in the future.

Type I hypersensitivity reactions have been previ-ously described as a side-effect of leuprolide. Our case is the first case of Type III hypersensitivity reaction caused by leuprolide. Early recognition of the signs and symptoms of serum sickness is very important as it will result in early diagnosis and avoid complications like glomerulonephritis and irreversible neurological damage. Our patient’s symptoms resolved with pred-nisone which was tapered over a week. The patient was advised to avoid leuprolide in the future. We urge physicians using leuprolide to be wary of the signs and symptoms of serum sickness and to stop

Table 1. Side effect profile of Leuprolide.Adverse reactions associated with leuprolide:Menopause (100%) in premenopausal women,Hot flashes and diaphoresis (50%),Testicular atrophy (20%),Gynaecomastia (3%),Erectile dysfunction (2%),Pituitary apoplexy,Osteoporosis.Adverse events reported in post-marketing surveillance:Anaphylactoid reactions or asthmatic process (incidence rate of about 0.002%),Fibromyalgia,Photosensitivity reactions,Rash (unspecified),Respiratory disorders,Seizures,Urticaria and weight gain.

Cut

aneo

us a

nd O

cula

r T

oxic

olog

y D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y C

DL

-UC

San

ta C

ruz

on 1

2/04

/14

For

pers

onal

use

onl

y.

Hypersensitivity vasculitis associated with leuprolide 227

leuprolide if such symptoms develop. Other GnRH analogues should also be avoided in patients who develop allergic reactions to leuprolide and alterna-tive therapy should be instituted.

Declaration of interest

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.

References

1. Huirne JAF, Lambalk CB. Gonadotropin-releasing-hormone-receptor antagonists. Lancet 2001;358:1793–803

2. Schally AV. Luteinizing hormone-releasing hormone ana-logs: their impact on the control of tumorigenesis. Peptides 1999;20:1247–62

3. www.accessdata.fda.gov/drugsatfda_docs/label/2009/019943s029,020011s036lbl.pdf. [Accessed June 05, 2009.

4. Sylvestre DL, Ravetch JV. Fc receptors initiate the Arthus reaction: redefining the inflammatory cascade. Science 1994;265:1095.

5. Slatore CG, Tilles SA. Sulfonamide hypersensitivity. Immunol Allergy Clin North Am 2004;24:477.

6. Boothpur R, Hardinger KL, Skelton RM, et al. Serum sick-ness after treatment with rabbit antithymocyte globulin in kidney transplant recipients with previous rabbit exposure. Am J Kidney Dis 2010;55:141.

7. Brucculeri M, Charlton M, Serur D. Serum sickness-like reaction associated with cefazolin. BMC Clin Pharmacol 2006;6:3

8. Dixon FJ, Cochrane CC. Immune complex injury. In: Samter M, ed. Immunological Diseases. 4th ed. New York: Little, Brown and Company. 1988:233.

9. Lawley TJ, Frank MM. Immune complexes and allergic dis-eases. In: Middleton E Jr, ed. Allergy Principles and Practice. 4th ed. St Louis, MO: Mosby. 1993:990.

10. Clark BM, Kotti GH, Shah AD, Conger NG. Severe serum sickness reaction to oral and intramuscular penicillin. Pharmacotherapy 2006;26:705.

Cut

aneo

us a

nd O

cula

r T

oxic

olog

y D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y C

DL

-UC

San

ta C

ruz

on 1

2/04

/14

For

pers

onal

use

onl

y.