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).1 Since it is commonly prescribed for both FDA-indicated and off-label uses, associated dermatologic adverse events merit careful consideration.2 In this study, we analyzed the US FDA Adverse Event Reporting System (FAERS) for common dermatologic adverse events associated with hydroxychloroquine.3
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 I.
Most common dermatologic adverse reaction associated with hydroxychloroquine (N = 9242)
| Adverse reactions | Patients, n (%) |
|---|---|
| Drug hypersensitivity/rash/rash, pruritic/drug eruption/dermatitis/rash, maculopapular/rash, erythematous/allergic dermatitis/erythema/toxic skin eruption/rash, macular/rash, popular/rash, vesicular | 5670 (61.4) |
| Pruritus | 526 (5.7) |
| Urticaria | 419 (4.5) |
| Psoriasis/pustular psoriasis/dermatitis psoriasiform | 297 (3.2) |
| 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) |
| Stevens-Johnson syndrome/toxic epidermal necrolysis | 135 (1.5) |
| Panniculitis | 119 (1.3) |
| Photosensitivity reaction | 116 (1.3) |
| Blister | 115 (1.2) |
| Angioedema | 114 (1.2) |
| Skin necrosis | 113 (1.2) |
| Oral mucosal exfoliation/mucosal inflammation/mucosal ulceration/oral mucosal blistering/mucosal erosion | 112 (1.2) |
| Hyperhidrosis | 111 (1.2) |
| Cutaneous vasculitis/vasculitis rash/hypersensitivity vasculitis | 87 (0.9) |
| Acute generalized exanthematous pustulosis | 80 (0.9) |
| Drug reaction with eosinophilia and systemic symptoms | 79 (0.8) |
| Erythema multiforme | 78 (0.8) |
| Dry skin/eczema | 76 (0.8) |
| Pemphigus | 73 (0.8) |
| Acne/acne cystic | 71 (0.8) |
| Ecchymosis/purpura/skin hemorrhage | 67 (0.7) |
| Alopecia/hair loss/hair texture abnormality/hair color changes | 47 (0.5) |
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 II.
Demographics of patients with dermatologic adverse reaction associated with hydroxychloroquine
| Characteristics | Patients, n (%) |
|---|---|
| Age (n = 5758) | |
| 0-1 mo | 28 (0.5) |
| 2 mo to 2 y | 0 (0.0) |
| 3-11 y | 47 (0.8) |
| 12-17 y | 95 (1.6) |
| 18-40 y | 1279 (22.2) |
| 41-64 y | 2669 (46.4) |
| 65-85 y | 1611 (28.0) |
| >85 y | 29 (0.5) |
| Sex (n = 8704) | |
| Female | 7287 (83.7) |
| Male | 1417 (16.3) |
| Indication (n = 9141) | |
| Rheumatoid arthritis | 7509 (82.1) |
| Mixed connective tissue disease | 590 (6.5) |
| Antiphospholipid syndrome | 365 (4.0) |
| Juvenile idiopathic arthritis | 130 (1.4) |
| Psoriatic arthropathy | 114 (1.2) |
| Fibromyalgia | 107 (1.2) |
| Dermatomyositis | 98 (1.1) |
| Adenomatous polyposis coli | 78 (0.9) |
| Systemic lupus erythematosus | 65 (0.7) |
| Ankylosing spondylitis | 55 (0.6) |
| Crohn's disease | 12 (1.2) |
| Sjögren syndrome | 10 (0.1) |
| Chronic cutaneous lupus erythematosus | 5 (0.1) |
| Behҫet disease | 3 (0.1) |
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.1 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).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 antimalarial; 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 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.6
Footnotes
Funding sources: None.
Conflicts of interest: None disclosed.
IRB approval status: not applicable.
Reprints not available from the authors.
References
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