Retrospective analysis of dermatologic adverse events associated with hydroxychloroquine reported to the US Food and Drug Administration
Authors: Shari R. Lipner, Yu Wang
Journal: Journal of the American Academy of Dermatology (2020)

To the Editor: Hydroxychloroquine is approved by the US Food and Drug Administration (FDA) for treatment of malaria, systemic lupus erythematosus, and rheumatoid arthritis (RA).1Sharma A.N. Mesinkovska N.A. Paravar T. Characterizing the adverse dermatologic effects of hydroxychloroquine: a systematic review.J Am Acad Dermatol. 2020; 83: 563-578Abstract Full Text Full Text PDF PubMed Scopus (71) Google Scholar Since it is commonly prescribed for both FDA-indicated and off-label uses, associated dermatologic adverse events merit careful consideration.2Living mapping and living systematic review of COVID-19 studies. Pharmacologic treatments for COVID-19 patients.https://covid-nma.com/living_data/index.phpDate accessed: June 23, 2020Google Scholar In this study, we analyzed the US FDA Adverse Event Reporting System (FAERS) for common dermatologic adverse events associated with hydroxychloroquine.3US Food and Drug AdministrationFDA adverse event reporting system.https://fis.fda.gov/sense/app/d10be6bb-494e-4cd2-82e4-0135608ddc13/sheet/33a0f68e-845c-48e2-bc81-8141c6aaf772/state/analysisDate accessed: June 23, 2020Google Scholar From January 1, 1970, to December 31, 2019, 28,220 adverse reactions associated with hydroxychloroquine/Plaquenil (Sanofi-Synthelabo Inc, Paris, Fance) were reported to FAERS, with 11,471 categorized as skin/subcutaneous tissue/mucosal disorders. After grouping similar reaction types and excluding events with fewer than 40 cases, 9242 remained for final analysis (Table I).Table IMost common dermatologic adverse reaction associated with hydroxychloroquine (N = 9242)Adverse reactionsPatients, n (%)Drug hypersensitivity/rash/rash, pruritic/drug eruption/dermatitis/rash, maculopapular/rash, erythematous/allergic dermatitis/erythema/toxic skin eruption/rash, macular/rash, popular/rash, vesicular5670 (61.4)Pruritus526 (5.7)Urticaria419 (4.5)Psoriasis/pustular psoriasis/dermatitis psoriasiform297 (3.2)Skin ulcer/skin fissures/skin erosion243 (2.6)Nail changes/onycholysis/onychomadesis/nail discoloration178 (1.9)Skin hyperpigmentation/pigmentation disorder/skin discoloration166 (1.8)Skin exfoliation/dermatitis exfoliative/dermatitis exfoliative generalized150 (1.6)Stevens-Johnson syndrome/toxic epidermal necrolysis135 (1.5)Panniculitis119 (1.3)Photosensitivity reaction116 (1.3)Blister115 (1.2)Angioedema114 (1.2)Skin necrosis113 (1.2)Oral mucosal exfoliation/mucosal inflammation/mucosal ulceration/oral mucosal blistering/mucosal erosion112 (1.2)Hyperhidrosis111 (1.2)Cutaneous vasculitis/vasculitis rash/hypersensitivity vasculitis87 (0.9)Acute generalized exanthematous pustulosis80 (0.9)Drug reaction with eosinophilia and systemic symptoms79 (0.8)Erythema multiforme78 (0.8)Dry skin/eczema76 (0.8)Pemphigus73 (0.8)Acne/acne cystic71 (0.8)Ecchymosis/purpura/skin hemorrhage67 (0.7)Alopecia/hair loss/hair texture abnormality/hair color changes47 (0.5) Open table in a new tab The most common reactions were drug hypersensitivity reactions/rash/dermatitis (5670 cases; 61.4%). Other relatively common events were pruritus and urticaria. Nail changes, skin hyperpigmentation, mucosal, and hair disorders represented 1.9% (n = 178), 1.8% (n = 166), 1.2% (n = 112), and 0.5% (n = 47) of cases, respectively. Serious dermatologic events including Stevens-Johnson syndrome/toxic epidermal necrolysis, skin necrosis, and vasculitis represented 335 cases (3.6%) (Table I). Ages were reported for 5758 patients, with most 41 to 64 years (46.4%) or 65 to 85 years old (28.0%). Sex was reported for 8704 individuals; most were female (7287; 83.7%) (Table II).Table IIDemographics of patients with dermatologic adverse reaction associated with hydroxychloroquineCharacteristicsPatients, n (%)Age (n = 5758) 0-1 mo28 (0.5) 2 mo to 2 y0 (0.0) 3-11 y47 (0.8) 12-17 y95 (1.6) 18-40 y1279 (22.2) 41-64 y2669 (46.4) 65-85 y1611 (28.0) >85 y29 (0.5)Sex (n = 8704) Female7287 (83.7) Male1417 (16.3)Indication (n = 9141) Rheumatoid arthritis7509 (82.1) Mixed connective tissue disease590 (6.5) Antiphospholipid syndrome365 (4.0) Juvenile idiopathic arthritis130 (1.4) Psoriatic arthropathy114 (1.2) Fibromyalgia107 (1.2) Dermatomyositis98 (1.1) Adenomatous polyposis coli78 (0.9) Systemic lupus erythematosus65 (0.7) Ankylosing spondylitis55 (0.6) Crohn's disease12 (1.2) Sjögren syndrome10 (0.1) Chronic cutaneous lupus erythematosus5 (0.1) Behҫet disease3 (0.1) Open table in a new tab These FAERS findings share some similarities with those in a systematic review of 689 hydrtplay @|Add/Remove Over/Underlayoxychloroquine-associated dermatologic events. In the review, the most common event was drug eruption (358 cases, 51.9%); pruritus (62; 8.9%) was relatively frequent.1Sharma A.N. Mesinkovska N.A. Paravar T. Characterizing the adverse dermatologic effects of hydroxychloroquine: a systematic review.J Am Acad Dermatol. 2020; 83: 563-578Abstract Full Text Full Text PDF PubMed Scopus (71) Google Scholar A notable difference was the high incidence of skin hyperpigmentation (116; 32.4%) in the systematic review versus FAERS (166; 1.8%). Nail changes were 5 times more common in FAERS, which is likely because the systematic review included only melanonychia cases. Although age and sex distributions were similar between the 2 studies, there were significant differences in drug indications. In the systematic review, the most common indications were lupus erythematosus (72%) and RA (14%), whereas in FAERS they were RA (82.1%), mixed connective tissue disease (6.5%), and antiphospholipid syndrome (4.0%) (Table II). The large difference in indications between the 2 studies is likely due to study design and estimated US disease prevalence (RA, 1,360,000; systemic lupus erythematosus, 322,000).4Centers for Diease Control and PerventionArthritis: national statistics.https://www.cdc.gov/arthritis/data_statistics/national-statistics.htmlDate accessed: June 23, 2020Google Scholar The most common adverse reaction in our data set was drug hypersensitivity/rash/dermatitis. Hydroxychloroquine-associated drug rashes typically ensue within 4 weeks of drug initiation and resolve after several weeks of drug discontinuation. Topical and oral steroids may mitigate symptomatic rashes. Patients may be switched to another antimalarial; desensitization or dose titration may be attempted if hydroxychloroquine is the best/only treatment option.5Takamasu E. Yokogawa N. Shimada K. Sugii S. Simple dose-escalation regimen for hydroxychloroquine-induced hypersensitivity reaction in patients with systemic lupus erythematosus enabled treatment resumption.Lupus. 2019; 28: 1473-1476Crossref PubMed Scopus (8) Google Scholar Patients with adverse events, including pruritus (526; 4.7%) and urticaria (419; 4.5%), may also benefit from dose escalation regimens. This study is subject to several limitations. FAERS data are self-reported by physicians, pharmaceutical companies, and patients, without corroboration. Some case information, dosing/cumulative dosing, and hydroxychloroquine prescribing by year were not available. Non-FDA indications for hydroxychloroquine (mixed connective tissue disease, antiphospholipid syndrome) were included in the data set. This study substantiates previous studies showing that drug rashes were the most common dermatologic adverse reaction with hydroxychloroquine. We also highlight some of the less frequent and more serious adverse reactions including Stevens-Johnson syndrome/toxic epidermal necrolysis, skin necrosis, and vasculitis.6Murphy M. Carmichael A.J. Fatal toxic epidermal necrolysis associated with hydroxychloroquine.Clin Exp Dermatol. 2001; 26: 457-458Crossref PubMed Scopus (43) Google Scholar