key: cord-0706260-5gorynd2
authors: Sachdeva, Muskaan; Mufti, Asfandyar; Maliyar, Khalad; Lytvyn, Yuliya; Yeung, Jensen
title: Hydroxychloroquine effects on psoriasis: a systematic review and a cautionary note for COVID-19 treatment
date: 2020-05-19
journal: J Am Acad Dermatol
DOI: 10.1016/j.jaad.2020.05.074
sha: 11ef91db55f226dbd66add939d45d48032226d48
doc_id: 706260
cord_uid: 5gorynd2

Abstract: Background While evidence suggests that hydroxychloroquine (HCQ) may decrease the viral load in patients with a COVID-19 infection, a number of case reports indicate adverse dermatologic effects of this potential treatment. Objective To conduct a systematic review of previously reported cases of psoriasis onset, exacerbation, or relapse after HCQ treatment. Methods A comprehensive EMBASE and MEDLINE search of original studies examining adverse effects of HCQ treatment related to psoriasis was conducted. Participant demographics, and details of HCQ administration and psoriasis diagnosis were extracted from 15 articles representing 18 patients. Results Females accounted for a significantly larger number of psoriatic cases compared to males and unreported sex (n=14, 77.8% vs. n=2, 11.1% vs n=2, 11.1% respectively). Additionally, 50% (n=9) of the cases did not have a history of psoriasis prior to taking HCQ. Of the 18 patients, 50.0% (n=9) experienced de novo psoriasis, 27.8% (n=5) experienced exacerbation of psoriatic symptoms and 22.2% (n=4) had a relapse of psoriasis after HCQ administration. Conclusions HCQ treatment may result in induction, exacerbation, or relapse of psoriasis. Monitoring for adverse effects of HCQ treatment is necessary, and clinical trials are essential in characterizing the safety profile of HCQ use in patients with a COVID-19 infection.

Hydroxychloroquine (HCQ) has been approved since 1955 for the prevention and treatment of malaria. 1 Since then, it's use has been extended to effectively treat a number of autoimmune disorders, 2 such as systemic lupus erythematosus 3, 4 and rheumatoid arthritis. 5 Evidence suggests that HCQ may also have potent antiviral properties. Such discovery prompted recent investigations for the potential use of this drug to treat patients with COVID-19, a novel infection caused by the severe acute respiratory syndrome coronavirus 2 (SARS CoV 2) initially reported in Wuhan, China in December 2019 6 and resulting in over 200,000 deaths worldwide by April, 2020. 7 Recent open-labeled, nonrandomized clinical trials showed that HCQ may decrease viral load and may improve outcomes in a small number of patients with COVID-19. [8] [9] [10] [11] Despite the lack of strong evidence, rapid spread of COVID-19 led the Food and Drug Administration (FDA) to approve emergency use of HCQ in hospitalized patients that do not have alternative treatment options. 12 However, the efficacy and safety profile of this drug are yet to be reported in ongoing randomized controlled trials. 13 A number of case reports indicate adverse dermatologic effects of HCQ treatment, such as new onset or exacerbation of psoriasis. Most recently, a 71-year-old patient with COVID-19 was reported to have an exacerbation of pre-existing psoriasis with silvery-scaled psoriatic plaques after 4 days of HCQ treatment. 14 As the incidence of COVID-19 infections increase, it is important for healthcare providers to recognize and manage the relevant adverse effects associated with potential HCQ treatment.

Therefore, the aim of this systematic review is to comprehensively summarize existing literature on the new onset, exacerbations or relapse of psoriasis after HCQ use. This will be an important step in assessing the potential dermatological impact of HCQ.

This systematic review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.

The search was conducted using the EMBASE and MEDLINE in OVID on April 21 st , 2020.

No language or date restrictions were applied. Variations of the following keywords were used for the search: "hydroxychloroquine", "plaquenil", "chloroquine" or "anti-malarial" in combination with "psoriasis", "plaque", "guttate", "pustular", "erythrodermic psoriasis" or "psoriatic".

Original articles that explored the effects of HCQ on psoriasis were included in this systematic review if they (i) involved human participants, (ii) were observational (i.e. case reports, case series, cross-sectional or cohort studies) or experimental (i.e. randomized controlled trials) studies, (iii) involved hydroxychloroquine as an intervention, (iv) included patients with psoriasis, and (v) were written in the English language.

Two reviewers (M.S and K.M.) independently screened titles, abstracts, and full texts of retrieved articles and determined study eligibility. Discrepancies or conflicts were resolved through discussion with a third reviewer (A.M.). Reference lists from all relevant articles were checked to identify additional studies not identified in the initial database search.

Reviewers (M.S and K.M.) independently reviewed and extracted data from each study using a structured form. Conflicts were reviewed collectively and if consensus was not reached, a third reviewer was consulted (A.M.). Study design, patient demographic data, dose and frequency of HCQ as well as details of psoriasis diagnosis and lesions were extracted and summarized in Table 1 . As there are no standardized response criteria for psoriatic lesions from HCQ use, we defined response as follows:

1. "Exacerbation" was defined as worsening of existing psoriasis, in terms of severity or lesion count, after administration of HCQ.

2. "Relapse" was defined as eruption of psoriatic lesions after administration of HCQ in individuals with past medical history of psoriasis.

3. "Induction" was defined as de novo eruption of psoriatic lesions after administration of HCQ, without current or past medical history of psoriasis.

Level of evidence for all included articles was assessed independently by two reviewers (M.S. and K.M.) using the Oxford Centre for Evidence-Based Medicine 2011 Levels of Evidence. 15 Due to the considerable heterogeneity of the included studies, a descriptive analysis was undertaken.

The search strategy described above yielded 354 records once duplicates were removed.

After screening the titles and abstracts for relevance, 55 records were selected for a full-text review. In total, 15 studies met eligibility criteria and were used for data collection and analysis of 18 patients (Figure 1 , Table 1 ). 14, [16] [17] [18] [19] [20] [21] [22] [23] [24] [25] [26] [27] [28] [29] The analysis of the level of evidence showed that 3 studies (20.0%) had a level of evidence of 4, 19,26,27 and 12 studies (80.0%) had a level of evidence of 5. 14, [16] [17] [18] [20] [21] [22] [23] [24] [25] 28, 29 Overall, patients were between 25 and 71 years of age.

Males accounted for 11.1% of cases (n=2), females accounted for 77.8% (n=14) and the sex of 2 cases was not reported (11.1%).

Eighteen patients reported psoriasis-related complications due to HCQ. Of these, 50% (n=9) did not have a history of psoriasis prior to taking HCQ, while 50.0% (n=9) had a psoriasis diagnosis prior to HCQ treatment. Psoriasis history was not reported for 1 patient (5.6%).

Comorbidities were present in 88.9% (n=16) of patients: 22.2% had systemic lupus erythematosus (n=4), 16.7% had rheumatoid arthritis (n=3), 16.7% had psoriatic arthritis (n=3), 11.1% had lichen planus (n=2), and 5.6% had Crohn's disease (n=1), COVID-19 (n=1), pemphigus erythematosus (n=1), mixed connective tissue disorder (n=1), polyarthralgia (n=1), and Primary Sjogren's syndrome (n=1), respectively.

Of the 18 patients, 50.0% (n=9) experienced de novo psoriasis, 27.8% (n=5) experienced exacerbation of psoriatic symptoms and 22.2% (n=4) had a relapse of psoriasis after HCQ administration. From the 9 de novo psoriasis cases, 33.3% had pustular (n=3), 11.1% inverse (n=1), 11.1% erythrodermic (n=1), and in 44.4% of cases the type of psoriasis was not recorded (NR, n=4). The type of psoriasis in the 9 cases experiencing exacerbation or relapse of psoriasis after HCQ treatment included: 22.2% pustular (n=2), 11.1% inverse (n=1), and NR in 66.7% (n=6). There was no pattern noted with regards to the location of the psoriatic lesions after HCQ use. Specifically, the distribution of lesions was found to be as follows:

38.9% (n=7), on the chest/abdomen, 33.3% (n=6) on the limbs and digits, 27.8% on the scalp (n=5), 22 .2% (n=4) on the face, 16 .77% (n=3) on the back groin/buttocks, and neck respectively. Four patients (22.2%) reported lesions covering the entire body.

Psoriasis is an auto-immune, chronic inflammatory skin disease that may be induced or exacerbated by HCQ, a synthetic anti-malarial drug commonly used for the treatment of autoimmune disorders such as systemic lupus erythematosus and rheumatoid arthritis. 1, 12, 25 In the 15 studies identified in literature which included 18 patients, the data demonstrated that 50.0% of patients experienced a new diagnosis of psoriasis and 50.0% of these patients experienced a relapse or an exacerbation of previously diagnosed psoriasis. In light of the potential for HCQ use to treat COVID-19 infections, 6, 30 it is important for healthcare providers to recognize the impact of HCQ on psoriasis onset, relapse or exacerbation.

Although the exact mechanisms by which antimalarial drugs are able to induce psoriatic flares are not completely understood, 19 several potential mechanisms have been implicated.

An in vitro study conducted by Wolf et al. 31 noted hyperproliferation and irregular keratinization on skin cultures induced by HCQ. This may be due to the inhibiting effect HCQ has on epidermal transglutaminase activity, which leads to an initial break in the epidermal barrier. The resulting epidermal proliferation aimed at barrier restoration may lead to the induction or worsening of psoriasis. 31 In addition, HCQ may promote the production of IL-17 via p38-dependant IL-23 release, resulting in increased keratinocyte growth. 32 Furthermore, they may interfere with cholesterol metabolism process, which is crucial for the structural and functional integrity of the stratum corneum. 33 Lastly, patients identified in this study were predominantly females (77.8%, n=14). Given that autoimmune diseases are more prevalent in females, role of sex hormones may be suggested. 34 There are several limitations to our systematic review that must be considered. Firstly, all summarized studies are case reports and case series. As a result, the lack of larger trials and observational nature of the studies limits the scope of analysis and generalizability of our findings to all patients using HCQ treatment. Additionally, it is difficult to attribute the development of psoriasis to HCQ use alone, as autoimmune comorbidities such as rheumatoid arthritis and systemic lupus erythematosus may predispose individuals to psoriasis due to dysregulation of common cytokines. [17] [18] It is important to note that 92.3% of the studied patients had comorbid conditions, with the autoimmune disorders rheumatoid arthritis (33.3%) and systemic lupus erythematosus (25.0%) being the two most significant.

As a result, it may be difficult to attribute causality between psoriatic development or exacerbation and HCQ use alone, as these autoimmune comorbidities may predispose individuals to psoriasis due to dysregulation of common cytokines such as Il-17 and IL-23. 35, 36 Furthermore, 33.3% of cases (n=6) reported in this systematic review were also taking oral steroids. Of these 6 cases, 2 developed de-novo erythrodermic psoriasis and pustular psoriasis respectively, and 1 experienced a relapse of pustular psoriasis. Given that oral steroids have been reported to induce or precipitate erythrodermic and pustular psoriasis, HCQ may not have been solely responsible for the induction or relapse of psoriasis in these cases. 37, 38 In addition to the known side-effects of HCQ, such as QT prolongation, conduction abnormalities and restrictive or dilated cardiomyopathy, 39, 40 it is also essential to understand the impact of HCQ on exacerbation, relapse or new onset of psoriatic lesions. Although no robust peer-reviewed evidence exits at this time, a recent news article reported a higher mortality rate (27.8%) among COVID-19 patients who were administered HCQ compared to those who were not (11.4%). 41 This article brought attention to the significance of awaiting further evidence prior to extensive promotion and acceptance of this drug. Additional studies examining the safety profile of HCQ, especially in patients with psoriasis are desperately needed, before its potential use for COVID-19 infection. Given the lack of rigorous evidence available, further studies with larger sample sizes are required to confirm the findings reported in this systematic review. Many randomized trials are actively recruiting participants to determine the safety profile of HCQ treatment in COVID-19 patients. [42] [43] [44] [45] [46] The results from these studies will be key to determining if HCQ treatment is significantly associated with exacerbation, relapse or new onset of psoriasis. 

Drug-induced psoriasis: clinical perspectives. Psoriasis: Targets and Therapy

Therapy and pharmacological properties of hydroxychloroquine and chloroquine in treatment of systemic lupus erythematosus

Hydroxychloroquine in systemic lupus erythematosus (SLE)

Hydroxychloroquine: a multifaceted treatment in lupus

Multifaceted effects of hydroxychloroquine in human disease. Seminars in Arthritis and Rheumatism

The origin, transmission and clinical therapies on coronavirus disease 2019 (COVID-19) outbreak -an update on the status

The transmission and diagnosis of 2019 novel coronavirus infection disease (COVID 19): A Chinese perspective

Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial

Breakthrough: chloroquine phosphate has shown apparent efficacy in treatment of COVID-19 associated pneumonia in clinical studies

Efficacy of hydroxychloroquine in patients with COVID-19: results of a randomized clinical trial

Therapeutic effect of hydroxychloroquine on novel coronavirus pneumonia (COVID-19). Chinese Clinical Trials Registry

Food and Drug Administration

Aminoquinolines against coronavirus disease 2019 (COVID-19): chloroquine or hydroxychloroquine

A case of exacerbation of psoriasis after oseltamivir and hydroxychloroquine in a patient with COVID-19: Will cases of psoriasis increase after COVID-19 pandemic?

Centre for Evidence-based Medicine -Levels of Evidence

Hydroxychloroquine-induced inverse psoriasis

Hydroxychloroquine-Induced Psoriasis-form Erythroderma in a Patient with Systemic Lupus Erythematosus

A case of generalized pustular psoriasis caused by hydroxychloroquine in a patient with systemic lupus erythematosus

Synthetic antimalarial drugs and the triggering of psoriasis-do we need disease specific guidelines for the management of patients with psoriasis at risk of malaria?

Development of drug-induced inverse psoriasis in a patient with Crohn's Disease

Plaquenil-induced erythroderma

Hydroxychloroquine de Novo-Induced Psoriasis in a Patient With Lichen Planus Pigmentosus

Pustular psoriasis associated with hydroxychloroquine

Generalized pustular drug rash induced by hydroxychloroquine

Exacerbation of Psoriasis due to Hydroxychloroquine

AB0827 Hydroxychloroquine Does not Increase Psoriasis in Psoriatic Arthritis: Time on Drug Analysis Based on Real Life Data

Coexistent psoriasis and lupus erythematosus: successful therapy with etretinate

Pustular psoriasis induced by hydroxychloroquine: A case report to confirm a rare association: 3734

Evolution of signs… rethink… rebiopsy: P2208

The epidemiology, diagnosis and treatment of COVID-19

The in vitro effect of hydroxychloroquine on skin morphology in psoriasis

Production by CD4+ T Cells via p38-Dependent IL-23 Release by Monocyte-Derived Langerhans-like Cells

Clinical efficacy and side effects of antimalarials in systemic lupus erythematosus: a systematic review

Current knowledge on psoriasis and autoimmune diseases

Autoimmunity and autoimmune co morbidities in psoriasis

Precipitation of generalized pustular psoriasis by prednisolone

An Uncommon Presentation of Erythrodermic Psoriasis in a Patient Without a History of Psoriasis

The association between hydroxychloroquine treatment and cardiovascular morbidity among rheumatoid arthritis patients

Hydroxychloroquine-Induced Pigmentation in Patients With Systemic Lupus Erythematosus

Study Finds No Benefit, Higher Death Rate In Patients Taking Hydroxychloroquine For Covid-19

Hydroxychloroquine Treatment for Severe COVID-19 Pulmonary Infection (HYDRA Trial) (HYDRA)

The PATCH Trial (Prevention And Treatment of COVID-19 With Hydroxychloroquine) (PATCH)

Identifier NCT04342221, Hydroxychloroquine for COVID-19 (COV-HCQ)

Identifier NCT04345692, A Randomized Controlled Clinical Trial: Hydroxychloroquine for the Treatment of COVID-19 in Hospitalized Patients (OAHU-COVID19)

Identifier NCT04333654, Hydroxychloroquine in Outpatient Adults With COVID-19)