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Leukocytoclastic VasculitisAssociated with NizatidineTherapyJung-Gon Suh, MD, Leslie Oleksowicz, MD,Janice P. Dutcher, MD, Montefiore Medical Center,Albert Einstein College of Medicine, Bronx, New York

Nizatidine is a histamine H2-receptor antagonistthat has recently been FDA approved for the

treatment of duodenal ulcers, benign gastric ulcers,and gastroesophageal reflux disease. Like otherprescription and over-the-counter H2-blockers, ni-zatidine has been extensively used with infrequentside effects. Although rare allergic reactions to thedrug have been reported,1 most nizatidine-associ-ated toxicities have been described as mild andwithout serious consequences. We describe a pa-tient who developed a serious, rapidly progressingleukocytoclastic vasculitis when treated with niza-tidine as prophylaxis against gastric ulceration dur-ing interleukin-2 (IL-2) therapy and also when laterrechallenged with this same H2-blocker. This is thefirst recognized case of leukocytoclastic vasculitisassociated with nizatidine administration.

CASE REPORTA 67-year-old male with a medical history signifi-

cant for hypertension, benign prostatic hypertrophy,and metastatic renal cell carcinoma was admitted formoderate-dose bolus interleukin-2 therapy. Hischronic medications consisted of atenalol, amlodi-pine besylate, doxazosin mesylate, alprazolam, andsertraline. On this present admission, the patient de-nied any antecedent viral infections, history of aller-gies, skin rashes, arthritis, or peripheral neuropa-thies.

During a prior cycle of IL-2 treatment, the patienthad developed rapid atrial fibrillation as an IL-2–as-sociated toxicity. Therefore, 2 days prior to IL-2 ad-ministration, the patient was instructed to discon-tinue his antihypertensive medications; he was givendigoxin and diltiazem and was also started on IL-2ancillary medications consisting of indocin 25 mg POevery 8 hours, acetaminophen 650 mg PO every 4hours, and nizatidine 150 mg PO twice daily. Ap-proximately 24 hours after the start of IL-2 treatmentand 3 days from the start of the ancillary medica-tions, an erythematous macular, papular rash ap-peared on the patient’s right thigh. Within 8 hours,the rash had spread to the contralateral leg, the dor-sal aspects of both feet, and the bilateral extensorsurfaces of both arms (Figure). The IL-2, indocin,

acetaminophen, nizatidine, digoxin, and diltiazemwere immediately discontinued. A skin biopsy dem-onstrated fibrinoid necrosis of the superficial dermalblood vessels with perivascular fibrin deposition anda perivascular infiltrate of mononuclear cells andneutrophils with leukocytoclasia. The patient dis-played no fever, pruritus, or constitutional symp-toms such as headache, nausea, vomiting, abdominalpain, arthralgia, or arthritis. Serum specimens werenegative for hepatitis, rheumatoid factor, cryoglob-ulins, and antinuclear antibodies. Total complementlevels and C’3 levels were within normal limits.

Within 24 hours, the rash ceased to progress, andwithin 48 hours, it started to dissipate. During thistime, no gross hematuria, microscopic hematuria,hemoptysis, or overt signs of hemorrhage were ob-served. After the patient was discharged, he was re-challenged with indocin, acetaminophen, nizatidine,digoxin, and diltiazam, individually, for 3 days. Onthe third day of nizatidine, an erythematous, papularrash developed on the patient’s right thigh that wasidentical to his prior cutaneous reaction. A rechal-lenge with the other suspect medications, includingIL-2, did not result in any dermatologic reactions,thereby identifying nizatidine as the causative agentfor the leukocytoclastic vasculitis.

DISCUSSIONAlthough the etiology of leukocytoclastic vasculi-

tis is unclear, this dermatologic reaction has beenassociated with systemic lupus, rheumatoid arthritis,mixed cryoglobulinemia, hepatitis infection, micro-bial infections and immunizations, and drugs.2-4 It isunlikely that this vasculitis was associated with anew-onset systemic disease as evidenced by thechronology of the patient’s clinical course and thenegative serology testing. The patient’s cutaneouseruptions first occurred approximately 72 hours af-ter the initiation of nizatidine and again 72 hours af-ter rechallenging with nizatidine as an outpatient.

A variety of drugs have been reported to be asso-ciated with hypersensitivity vasculitis and includepenicillin, sulfonamides and other antibiotics, non-steroid anti-inflamatory agents, propylthiouracil andiodides, levamisole, and anticonvulsants.3-7 Otherthan the nonsteroidal anti-inflammatory agent, thecalcium channel blocker, the cardiac glycoside, thesertraline antidepressant, and IL-2 have not previ-ously been described as a cause of a leukocytoclasticvasculitis. Although drug-induced leukocytoclasticvasculitides typically present from 1 to 3 weeks afterinitiation of the offending agent,8 in the present case,the rash appeared 72 hours after initiation of nizati-dine. A similar time course has also been reportedfor leukocytoclastic vasculitis associated with ci-metidine administration, ofloxicin administration,

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Figure. Nizatidine-induced vasculitis presenting as papules and plaques. A. Dependent aspect of lower extrem-ities (below knees) demonstrating clustering of papules. B. Lower extremities show vasculitic papules coalescingto form erythematous plaques on upper thighs. C. Raised extensor surface of forearms shows papules andplaques.

and retinoids.9-11 Additionally, an analysis of studiesreporting cutaneous toxicities directly attributableto H2-receptor antagonists demonstrates only twocases of hypersensitivity vasculitis reported in as-sociation with cimetidine9 and famotidine.12 As such,this evidence indicates that hypersensitivity vascu-litis can be a rare but serious toxicity resulting fromH2-receptor antagonist administration.

In conclusion, this case shows that a potentiallyserious vasculitic process can occur in associationwith nizatidine administration. With the understand-ing that systemic vasculitides may also effect vis-ceral organs and can be life-threatening, this caseillustrates the need for close monitoring of cutane-ous reactions in patients treated with nizatidine.

REFERENCES1. Mira-Perceval JL, Ortiz JL, Sarrio F, et al. Nizatidine anaphylaxis. J AllergyClin Immunol. 1996;97:855–856.2. Katz P. Hypersensitivity vasculitis. Am Fam Phys. 1982;26:171–175.3. Somer T, Finegold SM. Vasculitides associated with infection, immunizationand antimicrobial drugs. Clin Infect Dis. 1995;20:1010–1036.4. O’Brien WM, Bagby GF. Rare adverse reactions to nonsteroidal antiinflam-matory drugs. J Rheumatol. 1985;12:347–353.5. Verdy M, Pretty H, Cadotte M, et al. Vasculitis caused by antithyroid drugs.Union Med Can. 1975;104:576–579.6. MacFarlane DG, Bacon PA. Side effects of drugs. Levamisole-induced vas-culitis due to circulating immune complexes. BMJ. 1978;1:407–408.7. Shear NH, Spielberg SP. Anticonvulsant hypersensitivity syndrome: in vitroassessment of risk. J Clin Invest. 1988;82:1826–1832.8. Roujeau JC, Stern RS. Severe adverse cutaneous reactions to drugs. NEJM.1994;331:1272–1285.9. Mitchell GG, Magnusson AR, Weiler JM. Cimetidine-induced vasculitis. Am JMed. 1983;75:875–876.

10. Huminer D, Cohen JD, Majadla R, Dux S. Hypersensitivity vasculitis due toofloxacin. BMJ. 1989;299:303.11. Dwyer JM, Kenicer K, Taylor Thompson B, et al. Vasculitis and retinoids.Lancet. 1989;2:494–496.12. Andreo JA, Vivancos F, Lopez VM, Soriano J. Vasculitis leucocitoclastica yfamotidina. Med Clin (Barc). 1990;95:234–235.

Manuscript submitted June 27, 1996 andaccepted in revised form October 2, 1996.

Azithromycin-inducedIntrahepatic CholestasisGiuseppe Longo, MD, Chiara Valenti, MD,Giovanna Gandini, MD, Leonardo Ferrara, MD,Marcello Bertesi, MD, Giovanni Emilia, MD,University of Modena, Italy

Drug-induced intrahepatic cholestasis (either pureor cholestatic hepatitis) has been a known con-

dition for many years.1 The drugs most frequently in-volved are hormonal steroids, antibiotics (macrolides,penicillins, clavulanic acid), and psychopharmacolog-ical agents (phenothiazines and some antidepressants).The mechanisms underlying hepatotoxicity may be pri-marily metabolite dependent (isoniazid) or hypersen-sitivity mediated (beta-lactams), or may result fromboth processes (sulphonamides, erythromycin deriva-tives).2