Quetiapine‐Induced Cutaneous Vasculitis: Diagnostic Challenges and Therapeutic Implications

This is the authors' abstract. We don't add key points for this paper.

To the Editor: Guidelines recommend against the routine use of antipsychotics for behavioral and psychological symptoms of dementia (BPSDs), because clinical benefit is modest, and evidence mounts of potential harms.1 Although the risks of motor, metabolic, cerebrovascular, and cardiovascular events are well known, adverse cutaneous adverse drug reactions (ACDRs) to antipsychotics are less commonly reported, yet the consequences are no less significant. This is a report of an ACDR to the atypical antipsychotic quetiapine and its clinical implications. A 68-year-old Chinese woman was admitted to the hospital for a 1-week complaint of painful and itchy lower limb rash. She had been diagnosed with Alzheimer's disease 2 months before admission complicated by depression, paranoid delusions, visual hallucinations, and agitation. Because her behavior was severely distressing to herself and her family, she was started on quetiapine, an atypical antipsychotic. At admission, she was taking an oral medication regimen of donepezil 5 mg/d and quetiapine 12.5 mg in the morning and 25 mg at night, started 6 weeks before the onset of rash. The dose of quetiapine had been gradually increased in the preceding weeks. She also had a nightly dose of fluvoxamine 100 mg that had been initiated 4 months before. At admission, she was afebrile, and her vital signs were normal. An erythematous, raised, nonblanching rash was distributed across both shins, consistent with palpable purpura. Laboratory tests showed a borderline low leukocyte count (3.5 × 109/L). Eosinophil count, serum creatinine, transaminases, and C-reactive protein levels were normal. History and physical examination was not suggestive of connective tissue disease, nor was she taking any new drugs. Tests for complement C3, C4, antinuclear antibodies, antidouble-stranded deoxyribonucleic acid, anti-Ro, anti-La, anti-ribonucleoprotein, anti-Sm, anti-Jo1, anti-SCl 70, and antineutrophil cytoplasmic antibodies were negative. Adjustments were made to her medications because worsening BPSDs were observed. Donepezil was withheld, and quetiapine dose was gradually increased to 50 mg twice a day. As the dose of quetiapine was increased, the purpuric rash appeared to worsen. Subsequent punch biopsy of the skin rash showed superficial perivascular lymphocytic infiltrate and focal red cell extravasation around upper dermal blood vessels. Direct immunofluorescence revealed granular deposits of immunoglobulin M and C3 within the walls of the upper dermal vessels, consistent with vasculitis. The etiology of cutaneous vasculitis was postulated to be drug related, possibly due to quetiapine. Quetiapine was withheld, and the patient was given haloperidol and, later, risperidone. She did not receive corticosteroids. Her rash gradually improved and resolved by the seventh day after stopping quetiapine. ACDRs to antipsychotics have been reported to occur in approximately 5% of individuals.2 Although most are benign, some can be severe and life-threatening, including Stevens-Johnson syndrome, drug rash with eosinophilia and systemic symptoms, and drug hypersensitivity vasculitis. In previous studies, cutaneous hypersensitivity vasculitis has been found to be associated with clozapine,3 haloperidol,4 and olanzapine.5 Switching from oral to long-acting intramuscular formulations of antipsychotics is a risk factor for development of drug rash.6 A challenge in diagnosing drug-associated disease is causality assessment. In this instance, worsening rash with increase in dose and resolution on discontinuation of quetiapine suggested quetiapine as the culprit. The interval from drug exposure to appearance of symptoms for drug-induced vasculitis is variable, with onset of symptoms occurring months after drug exposure.7 Applying the Naranjo Adverse Drug Reactions Probability Scale8 would yield a score of +7, indicating a likelihood of a probable adverse drug reaction. To the knowledge of the authors, this is the first report of quetiapine-induced vasculitis. Prompt identification and withdrawal of the offending drug is a priority in management. Corticosteroids may be indicated in more-severe cases of hypersensitivity vasculitis, but their neuropsychiatric sequelae need to be considered before initiation of therapy. Treatment with systemic immunosuppressive therapy may be warranted for refractory disease. Care should be taken to assess safety before discontinuation of medication, and appropriate alternatives need to be considered because of the potential for cross-reactivity. In this woman, haloperidol and risperidone were given safely. Olanzapine and clozapine were avoided because of their structural similarity to quetiapine,9 although cross-reactivity has been reported with olanzapine and risperidone,10 underscoring the need for careful monitoring because the risk of skin reactions to different chemical classes can be unpredictable. This case highlights the diagnostic challenges and therapeutic implications of a rare adverse reaction to a drug prescribed off label for the pharmacological treatment of BPSDs. A high index of suspicion should be maintained for drug-related causes of cutaneous small vessel vasculitis. Given the potential morbidity associated with use of antipsychotics, a careful balance needs to be struck between benefits of symptom control and development of adverse effects. Conflict of Interest: The editor in chief has reviewed the conflict of interest checklist provided by the authors and has determined that the authors have no financial or any other kind of personal conflicts with this paper. Author Contributions: All authors were involved in the care of the woman and contributed to the manuscript. Sponsor's Role: None.