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 Table of Contents    
Year : 2019  |  Volume : 61  |  Issue : 1  |  Page : 94-96
Leukocytoclastic vasculitis secondary to clozapine

1 Department of Clinical and Experimental Pharmacology, School of Tropical Medicine, Kolkata, West Bengal, India
2 Department of Pharmacology, MGM Medical College and LSK Hospital, Kishanganj, Bihar, India
3 Department of Pathology, MGM Medical College and LSK Hospital, Kishanganj, Bihar, India

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Date of Web Publication9-Jan-2019


Leukocytoclastic vasculitis (LCV) may be secondary to drugs, underlying infection, collagen vascular disorders, or malignancy. Drug-induced vasculitis contributes to 10% of vasculitic skin lesions cases usually developing within 7–21 days of treatment initiation. The present case highlights a report of LCV in a 59-year-old male with a history of paranoid schizophrenia on clozapine therapy. The report upsurges the need to promote awareness and expedite diagnosis and treatment of drug-induced LCVs.

Keywords: Clozapine, leukocytoclastic vasculitis, pharmacovigilance

How to cite this article:
Mukherjee S, Era N, Mukherjee M, Tripathi SK. Leukocytoclastic vasculitis secondary to clozapine. Indian J Psychiatry 2019;61:94-6

How to cite this URL:
Mukherjee S, Era N, Mukherjee M, Tripathi SK. Leukocytoclastic vasculitis secondary to clozapine. Indian J Psychiatry [serial online] 2019 [cited 2022 Nov 28];61:94-6. Available from:

   Introduction Top

Vasculitis is a term used for a heterogeneous group of clinical conditions with a common feature of vessel inflammation and is characterized by fibrinoid necrosis, thrombosis, and sometimes a granulomatous reaction. Vascular damage may occur in venules, capillaries, and arterioles, causing local and systemic clinical manifestations, depending on the organs involved, thus presenting with varied signs and symptoms.[1] Leukocytoclastic vasculitis (LCV), also referred as hypersensitivity vasculitis and hypersensitivity angiitis, is a histopathologic term commonly used to denote a small-vessel vasculitis. Patients with LCV generally have a good prognosis; however, if kidneys, gastrointestinal tract, lungs, heart, or central nervous system are involved, morbidity may increase and mortality can occur. Cutaneous lesions of LCV are mostly asymptomatic, but they may be associated with pruritus or pain. Bullous lesions, as well as chronic cutaneous disease, may involve ulceration or painful episodes of purpura, which may cause physical limitations.[2] While classical presentation includes palpable purpura, lesser common clinical findings involve urticarial plaques, vesicles, bullae, and pustules. Histologically, LCV is characterized by leukocytoclasis, which refers to vascular damage caused by nuclear debris from infiltrating neutrophils. LCV may be localized to the skin or may be associated with systemic involvement.[3]

LCV may be secondary to drugs, underlying infection, collagen vascular disorders, or malignancy. However, approximately half of the cases are idiopathic.[4],[5],[6] Drug-induced vasculitis contributes to 10% of vasculitic skin lesion cases, and it usually develops within 7–21 days of treatment initiation.[7] The severity of these reactions can range from mild and self-limiting grade to a severely progressive and even a fatal one. The present report describes a case of clozapine-induced LCV.

   Case Report Top

A 59-year-old male reported with complaints of arthralgia, myalgia, and skin rash on his legs. The rash was examined as confluent, palpable erythematous nonblanchable purpura. On history elicitation, the patient reported being diagnosed with paranoid schizophrenia (Diagnostic and Statistical Manual of Mental Disorders [DSM]-IV) 8 years ago, for which he was admitted and was treated with haloperidol (2 mg intravenous [IV]) along with benztropine 1 mg IV, divalproex sodium 500 mg once daily (OD), and lorazepam 4 mg IV. At the time of discharge, for about 2 weeks, the patient was continued on oral haloperidol 5 mg twice daily and divalproex sodium 500 mg OD. After 7 years of therapy with haloperidol, he developed typical choreiform and athetoid bucco-oro-masticatory movements characterized by lip smacking, puffing of cheeks, and fly catching motion of tongue. A provisional diagnosis of tardive dyskinesia, based on the DSM-V criteria, was made, and a dose of haloperidol was tapered. With nonresolvement of symptoms in subsequent visits, haloperidol was finally discontinued and clozapine was initiated 17 days earlier to the present date of reporting. His dose was slowly uptitrated. When the total dose of clozapine was 137.5 mg/day, he developed this rash on his legs. The rash continued to spread up to his lower extremities. He was afebrile with stable vital signs and had a benign examination otherwise.

The initial differential diagnoses included Rocky Mountain spotted fever, Churg–Strauss syndrome, Wegener's granulomatosis, microscopic polyarteritis, mixed cryoglobulinemia, and Henoch-Schönlein purpura. The patient was empirically administered doxycycline in case of Rocky Mountain spotted fever, and his divalproex sodium and clozapine doses were held steady. Rocky Mountain spotted fever was ruled out by serology. Churg–Strauss syndrome was unlikely because he did not have a history of asthma or eosinophilia. The results of urine and blood cultures and serologies consisting of complete blood count, liver function tests, creatine kinase, and erythrocyte sedimentation rate were all under the routine limits. He was managed conservatively without steroids and underwent further serological testing including serum cryoglobulins, complement C3, complement C4, hepatitis C, and antineutrophil cytoplasmic antibodies tests, whose results were found negative. Histopathology shows subepidermal blister with vascular damage affecting mainly small vessels of the dermis and is characterized by predominately neutrophilic infiltrate along other mononuclear infiltrate, and there is fragmentation of nuclei (karyorrhexis), with swelling of endothelial cells with fibrin deposit, suggestive of LCV [Figure 1] and [Figure 2]. Since clozapine was the only recently added medication, a physician decided to dechallenge this medication. The patient gradually improved with conservative management. However, no rechallenge was attempted. The temporal relationship between clozapine and small-vessel vasculitis was thus made.
Figure 1: Histopathologic examination revealing blister formation

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Figure 2: Histopathology showing vascular damage and neutrophilic infiltrate and fibrin deposit

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Causality assessment of the reaction conferred it to be “probable” with a score of 5 using Naranjo's causality assessment algorithm,[8] while the WHO–UMC causality assessment scale[9] graded it as probable or likely. Severity assessment using Hartwig–Siegels Scale[10] conferred it to be moderate (Level 4). The event was reported under the Pharmacovigilance Programme of India.

   Discussion Top

Small-vessel vasculitis refers to inflammation in the walls of the small vessels. Conventionally, these are cutaneous blood vessels. The classic phenotypic manifestation of small-vessel vasculitis is palpable purpura; however, this is often not present. The histopathologic features of the vessel wall inflammation are important in defining the nature of the vasculitis.[11]

The hallmark histopathologic pattern of small-vessel vasculitis is LCV; however, a lymphocytic form has also been described whose etiology or clinical relevance is still unclear.[11] During the initial disease phase, monocytes and plasmocytes remain the predominant infiltrates without fibrinoid necrosis or the nuclear fragments, a characteristic of LCV.[12] Old lesions of small-vessel vasculitis may no longer demonstrate LCV and may contain mainly lymphocytes around blood vessels. This later consideration stresses the importance of the timing when taking a biopsy in a dynamic process such as the vasculitic one.

LCV is characterized by angiocentric segmental inflammation, endothelial cell swelling, fibrinoid necrosis of blood vessel walls, and a cellular infiltrate around and within dermal blood vessel walls composed largely of the neutrophils showing the fragmentation of the nuclei. Erythrocyte extravasation is another key feature.[13]

The clinical picture of vasculitis is majorly dependent on the extent of vascular bed involvement, delay in diagnosis, and treatment. These heterogeneous clinical manifestations, combined with the etiologic nonspecificity of the histologic lesions, complicate the diagnosis of a specific form of vasculitis. Clozapine is the drug of choice for schizophrenia patients with persistent residual symptoms. Clozapine-induced vasculitis is a rare and serious complication that should be added to the adverse reaction profile of the clozapine therapy. The present report attempts to promote awareness and expedite diagnosis and treatment of this reaction.

The duration between exposure to a causative agent and subsequent development of vasculitis is extremely variable, ranging from hours to years. It is, therefore, difficult to ascertain an exact period after which drug-induced vasculitis is likely to commonly manifest. In most instances, however, the onset of drug-induced vasculitis typically occurs from 1 to 3 weeks after drug initiation. It is imperative for clinicians to be aware that drug-induced vasculitis can occur after increasing the dose of a medication or a rechallenge of the offending drug.[14],[15] Prompt withdrawal of the offending drug may resolve the severity to the possible extent.

Declaration of patient consent

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


We acknowledge and support the untiring efforts and the contribution of the Pharmacovigilance Programme of India toward ensuring better patient safety nationwide.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

   References Top

Iglesias-Gamarra A, Restrepo JF, Matteson EL. Small-vessel vasculitis. Curr Rheumatol Rep 2007;9:304-11.  Back to cited text no. 1
Gota CE, Calabrese LH. Diagnosis and treatment of cutaneous leukocytoclastic vasculitis. Int J Clin Rheumatol 2013;8:49-60.  Back to cited text no. 2
Jennette JC, Falk RJ. Small-vessel vasculitis. N Engl J Med 1997;337:1512-23.  Back to cited text no. 3
Aounallah A, Arouss A, Ghariani N, Saidi W, Sriha B, Denguezli M, et al. Cutaneous leukocytoclastic vasculitis: About 85 cases. Pan Afr Med J 2017;26:138.  Back to cited text no. 4
Lotti T, Ghersetich I, Comacchi C, Jorizzo JL. Cutaneous small-vessel vasculitis. J Am Acad Dermatol 1998;39:667-87.  Back to cited text no. 5
Tai YJ, Chong AH, Williams RA, Cumming S, Kelly RI. Retrospective analysis of adult patients with cutaneous leukocytoclastic vasculitis. Australas J Dermatol 2006;47:92-6.  Back to cited text no. 6
Naziha K, Dorsaf M, Maha BS, Mohsen H. Cutaneous vasculitis induced by Rifampicin. Egypt Dermatol Online J 2010;6:1-5.  Back to cited text no. 7
Naranjo CA, Busto U, Sellers EM, Sandor P, Ruiz I, Roberts EA, et al. Amethod for estimating the probability of adverse drug reactions. Clin Pharmacol Ther 1981;30:239-45.  Back to cited text no. 8
The use of the WHO-UMC System for Standardised Case Causality Assessment. Available from: [Last accessed on 2018 Feb 13].  Back to cited text no. 9
Hartwig SC, Siegel J, Schneider PJ. Preventability and severity assessment in reporting adverse drug reactions. Am J Hosp Pharm 1992;49:2229-32.  Back to cited text no. 10
Iglesias Gamarra A, Matteson EL, Restrepo JF. Small vessel vasculitis history, classification, etiology, histopathology, clinic, diagnosis and treatment. Rev Colombiana Reumatol 2007;14:187-205.  Back to cited text no. 11
Suresh E. Diagnostic approach to patients with suspected vasculitis. Postgrad Med J 2006;82:483-8.  Back to cited text no. 12
Lotti TM, Comacchi C, Ghersetich I. Cutaneous necrotizing vasculitis. Relation to systemic disease. Adv Exp Med Biol. 1999;455:115-25.  Back to cited text no. 13
ten Holder SM, Joy MS, Falk RJ. Cutaneous and systemic manifestations of drug-induced vasculitis. Ann Pharmacother 2002;36:130-47.  Back to cited text no. 14
Singh G, Hodgson T, Clarke DE. Leukocytoclastic vasculitis secondary to pyridostigmine (Mestinon): Report of a possible first case. Perm J 2017;21. pii: 15-240.  Back to cited text no. 15

Correspondence Address:
Shatavisa Mukherjee
Department of Clinical and Experimental Pharmacology, School of Tropical Medicine, Kolkata - 700 073, West Bengal
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/psychiatry.IndianJPsychiatry_384_18

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  [Figure 1], [Figure 2]