key: cord-0906697-3tnhq9ll
authors: Lipner, Shari R.; Wang, Yu
title: Retrospective Analysis of Dermatological Adverse Events Associated with Hydroxychloroquine Reported to the United States Food and Drug Administration
date: 2020-07-08
journal: J Am Acad Dermatol
DOI: 10.1016/j.jaad.2020.07.007
sha: e51b6dba4eac4349075fdd4ddfe0de5afca46d5d
doc_id: 906697
cord_uid: 3tnhq9ll

nan

Hydroxychloroquine is Food and Drug Administration (FDA) approved for treatment of malaria, systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) [1] . Since it is commonly prescribed for both FDA-indicated and off-label uses, associated dermatological adverse events merit careful consideration. [2] In this study, we analyzed the United States (US) FDA Adverse Event Reporting System (FAERS) for common dermatological adverse events associated with hydroxychloroquine [3] . From 1/1/1970 to 12/31/2019, 28220 adverse reactions associated with hydroxychloroquine/Plaquenil were reported to FAERS, with 11471 categorized as skin/subcutaneous tissue/mucosal disorders. After grouping similar reaction types and excluding events with <40 cases, 9242 remained for final analysis ( Table 1 ).

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% (178), 1.8% (166), 1.2% (112), and 0.5 (47) of cases, respectively. Serious dermatologic events including Steven-Johnson Syndrome/Toxic Epidermal Necrolysis (SJS-TEN), skin necrosis, and vasculitis, represented 335 cases (3.6%) ( Table 1) . Ages were reported for 5758 patients, with most 41-64 (46.4%) or 65-85 years (28.0%). Sex was reported for 8704 subjects; most were female (7287, 83.7%) ( Table 2) .

These FAERS findings share some similarities with those in a systematic review of 689 hydroxychloroquine-associated dermatologic events. In the review, the most common event was drug eruption (358 cases, 51.9%); pruritus (62, 8.9%) was relatively frequent [1] . A notable difference was the high incidence of skin hyperpigmentation (116, 32.4%) in the systematic review vs. FAERS (166, 1.8%%). Nail changes were 5 times more common in FAERS, which is likely because the systematic review included only melanonychia cases. While age and sex distributions were similar between the two studies, there were significant differences in drug indication. In the systematic review, the most common indications were LE (72%) and RA (14%), while in FAERS they were RA (82.1%), mixed connective tissue disease (MCTD) (6.5%), and antiphospholipid syndrome (APLS) (4.0%) ( Table 2 ). The large difference in indications between the two studies is likely due to study design and estimated US disease prevalence (1, 360, 000 RA, 322, 000 SLE) [4].

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 anti-malarial; desensitization or dose titration may be attempted if hydroxychloroquine is the best/only treatment option [5] . 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 is 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 (MCTD, APLS) were included in the data set.

This study substantiates previous studies showing that drug rashes were the most common dermatological adverse reaction with hydroxychloroquine. We also highlight some of the less frequent and more serious adverse reactions including SJS-TEN, skin necrosis, and vasculitis [6] . Hydroxychloroquine is Food and Drug Administration (FDA) approved for treatment of malaria, systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) [1] . Since it is commonly prescribed for both FDA-indicated and off-label uses, associated dermatological adverse events merit careful consideration.

[2] In this study, we analyzed the United States (US) FDA Adverse Event Reporting System (FAERS) for common dermatological adverse events associated with hydroxychloroquine [3] . These FAERS findings share some similarities with those in a systematic review of 689 hydroxychloroquine-associated dermatologic events. In the review, the most common event was drug eruption (358 cases, 51.9%); pruritus (62, 8.9%) was relatively frequent [1] . A notable difference was the high incidence of skin hyperpigmentation (116, 32.4%) in the systematic review vs. FAERS (166, 1.8%%). Nail changes were 5 times more common in FAERS, which is likely because the systematic review included only melanonychia cases. While age and sex distributions were similar between the two studies, there were significant differences in drug indication. In the systematic review, the most common indications were LE (72%) and RA (14%), while in FAERS they were RA (82.1%), mixed connective tissue disease (MCTD) (6.5%), and antiphospholipid syndrome (APLS) (4.0%) ( Table 2 ). The large difference in indications between the two studies is likely due to study design and estimated US disease prevalence (1, 360, 000 RA, 322, 000 SLE) [4].

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 anti-malarial; desensitization or dose titration may be attempted if hydroxychloroquine is the best/only treatment option [5] . 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 is 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 (MCTD, APLS) were included in the data set.

Living mapping and living systematic review of Covid-19 studies. Pharmacologic Treatments for COVID-19 Patients

Food and Drug Administration Adverse Event Reporting System

Simple dose-escalation regimen for hydroxychloroquine-induced hypersensitivity reaction in patients with systemic lupus erythematosus enabled treatment resumption

Fatal toxic epidermal necrolysis associated with hydroxychloroquine

2%) Skin Ulcer/Skin Fissures/Skin Erosion 243 (2.6%)

Nail Changes/Onycholysis/Onychomadesis/Nail Discoloration 178 (1.9%)

Skin Hyperpigmentation/Pigmentation Disorder/Skin Discoloration 166 (1.8%)

Skin Exfoliation/Dermatitis Exfoliative/Dermatitis Exfoliative Generalized 150 (1.6%)

This study substantiates previous studies showing that drug rashes were the most common dermatological adverse reaction with hydroxychloroquine. We also highlight some of the less frequent and more serious adverse reactions including SJS-TEN, skin necrosis, and vasculitis [6] . Table   Novel