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Vol. 113. Núm. 2.
Páginas T166-T175 (Febrero 2022)
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Vol. 113. Núm. 2.
Páginas T166-T175 (Febrero 2022)
Practical Dermatology
Open Access
[Translated article] Hydroxychloroquine: An Essential Drug in Dermatology and Its Controversial Use in COVID-19
La hidroxicloroquina como fármaco fundamental en dermatología y su papel controvertido en la COVID-19
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D. Morgado-Carrascoa,
Autor para correspondencia
morgadodaniel8@gmail.com

Corresponding author.
, J. Ibaceta-Ayalab, J. Piquero-Casalsc
a Servicio de Dermatología, Hospital Clínic, Universitat de Barcelona, Barcelona, Spain
b Integramédica, Redsalud, Santiago, Chile
c Dermik, Clínica Dermatológica Multidisciplinar, Barcelona, Spain
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D. Morgado-Carrasco, J. Ibaceta-Ayala, J. Piquero-Casals
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Figuras (1)
Tablas (7)
Table 1. Pharmacokinetics of Hydroxychloroquine.
Table 2. Mechanism of Action of Hydroxychloroquine.
Table 3. Risk Factors For Hydroxychloroquine-Induced Retinopathy.
Table 4. Potential Adverse Effects of Hydroxychloroquine.
Table 5. Hydroxychloroquine in Clinical Practice: Dose, Monitoring, and Precautions.
Table 6. Main Clinical Studies on the Use of Hydroxychloroquine in Cutaneous Lupus Erythematosusa.
Table 7. Off-Label Use of Hydroxychloroquine in Dermatology and Type of Study Supporting it for Each Disease.
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Abstract

Hydroxychloroquine is an antimalarial drug with immunomodulatory, anti-inflammatory, antibacterial, and antiviral properties. It has a good safety profile, can be used in children and in pregnant and breastfeeding women, and does not suppress the immune system. Regular screening for retinopathy, one of the drug’s most feared adverse effects, is necessary. Hydroxychloroquine is a widely used, essential drug in dermatology. Clinical response rates are good in lupus erythematous, where it is a first-line therapy, as well in numerous autoimmune/inflammatory diseases, including lichen planus, polymorphic light eruption, porphyria cutanea tarda, granuloma annulare, and sarcoidosis. In 2020, it was widely prescribed both to prevent and to treat COVID-19 caused by SARS-CoV-2. Its increased use led to serious supply shortages and in some cases stocks were entirely depleted. Recent meta-analyses have concluded that hydroxychloroquine is ineffective against COVID-19 and have advised against its use.

Keywords:
Hydroxychloroquine
Dermatology
Lupus erythematosus
Lichen planus
COVID-19
Supply shortages
Resumen

La hidroxicloroquina es un antimalárico con acción inmunomoduladora, antiinflamatoria, antibacteriana y antiviral. Posee un buen perfil de seguridad y puede ser utilizada en niños, en mujeres embarazadas o durante la lactancia, y no produce inmunosupresión. La retinopatía es uno de sus efectos adversos más temidos y requiere controles regulares. La hidroxicloroquina es un fármaco esencial en dermatología, utilizado ampliamente con buenas tasas de respuesta clínica tanto como un tratamiento de primera línea en el lupus eritematoso, como en múltiples dermatosis autoinmunes/inflamatorias como liquen plano, erupción polimorfa lumínica, porfiria cutánea tarda, granuloma anular y sarcoidosis, entre otras. Durante el año 2020 fue prescrita a gran escala como profilaxis y tratamiento de la infección producida por el coronavirus SARS-CoV-2 (COVID-19). El aumento de la utilización de hidroxicloroquina produjo serias dificultades para su obtención e incluso desabastecimiento. En metaanálisis recientes se ha concluido que la hidroxicloroquina no es efectiva para el tratamiento de esta patología y se desaconseja su prescripción.

Palabras clave:
Hidroxicloroquina
Dermatología
Lupus eritematoso
Liquen plano
COVID-19
Desabastecimiento
Texto completo
Introduction

Hydroxychloroquine is an antimalarial drug derived from chloroquine. It is inexpensive and has a favorable safety profile1. Hydroxychloroquine has immunomodulatory, anti-inflammatory, and photoprotective properties, although it can act as a photosensitizer. In dermatology, it is a first-line agent for the treatment of lupus erythematosus and is widely used off-label in multiple autoimmune and inflammatory skin diseases (Fig. 1)1–3. Its antibacterial, antifungal, and antiviral properties led it to be prescribed off-label for the prophylaxis and treatment of SARS-CoV-2 infection (COVID-19)4,5. The increased use of hydroxychloroquine in this setting led to difficulties obtaining the drug and even temporary depletion of stocks. The present review examines the use of hydroxychloroquine in dermatology, its mechanism of action and toxicities, and the threat that COVID-19 constituted for the supply of the drug.

Figure 1.

Hydroxychloroquine in dermatology.

(0,15MB).
Pharmacokinetics and Mechanisms of Action

Hydroxychloroquine has high oral bioavailability, with 45% eliminated via the kidneys3. It is metabolized by cytochrome P450, although its plasma levels are not affected by inducers or inhibitors of this enzyme2 (Table 1).

Table 1.

Pharmacokinetics of Hydroxychloroquine.

Rapidly absorbed in the gastrointestinal tract 
High oral bioavailability (75%-100%) 
Long half-lifea 
Cutaneous levels 100- to 200-fold higher than in plasma 
Excreted via the kidneys (45%) and gastrointestinal tract (20%) 
Alkalinization of urine increases excretion 
Metabolized by cytochrome P450 
Plasma levels are not affected by cytochrome P450 inducers or inhibitors 

Source: Chew et al.2, Sardana et al.3, Fernandez1.

a

The long half-life of hydroxychloroquine makes it possible to prescribe different doses on alternate days. For example, to prescribe 300 mg/d, doses of 400 mg/d can be alternated with 200 mg/d.

The mechanism of action of hydroxychloroquine is complex. Its immunomodulatory effect stems from the inhibition of antigen presentation via the major histocompatibility complex, stabilization of lysosomal membranes, reduced cell-mediated cytotoxicity, and inhibition of multiple intracellular toll-like receptors3. Its anti-inflammatory effect is secondary to inhibition of phospholipase A2 and C and of various cytokines (tumor necrosis factor α, interferon α and γ, and interleukin [IL] 1, 2, and 6)2, and its photoprotective effect is secondary to its antioxidant and DNA-stabilizing properties, as well as to reduced levels of interleukins after UV radiation (Table 2)3. Hydroxychloroquine also diminishes survival of viruses, bacteria, and fungi in lysosomes and endosomes3.

Table 2.

Mechanism of Action of Hydroxychloroquine.

Immunomodulatory action  Inhibits antigen presentation via the major histocompatibility complex 
  Stabilizes lysosomal membranes 
  Diminishes cell-mediated cytotoxicity 
  Inhibits multiple intracellular toll-like receptors 
Anti-inflammatory action  Inhibits interleukin 1, 2, and 6, tumor necrosis factor α, and interferon α and γ 
  Reduces phospholipase A2 and C and synthesis of prostaglandins 
Photoprotective action  Presents antioxidant properties and protects from damage by free radicals induced by UV radiation 
  Absorbs UV radiation 
  Binds to DNA, thus stabilizing it 
  Regulates RNA transcription 
  Reduces levels of interleukin after UV irradiation 
  Reduces antigen presentation in irradiated skin 
Antibacterial and antiviral action  Alkalinizes intracellular organelles and phagosomes, thus reducing growth and survival of intracellular bacteria and viruses 
  Boosts intracellular action of antibiotics 
  Inhibits posttranslational modification of viral proteins 
  Inhibits production of sialic acid 
Antithrombotic action  Inhibits platelet aggregation and adhesion 
  Increases endothelium-mediated vasodilation 
  Inhibits formation of antiphospholipid antibodies 
Lipid-lowering action  Increases the amount of LDL receptors 
  Increases excretion of lipids 
Hypoglycemic action  Increases secretion of insulin 
  Increases sensitivity to insulin 

Source: Chew et al.2, Sardana et al.3.

Approved Indications in Dermatology

Hydroxychloroquine is approved by the United States Food and Drug Administration and the European Medicines Agency for the treatment of lupus erythematosus.

Adverse Events and Toxicity

Hydroxychloroquine has a favorable safety profile and is rarely discontinued owing to adverse effects. Retinal toxicity, one of the most feared effects, has been observed in 7.5% of patients, although it is extremely rare during the first 5 years of treatment. Doses greater than 5 mg/kg/d for more than 10 years are associated with an increased rate of retinopathy (Table 3)6. Gastrointestinal adverse effects are relatively common and include anorexia, heartburn, diarrhea, and abdominal distension3. The most common cutaneous adverse effects are rash, hyperpigmentation, and pruritis, as well as photosensitivity. Other, uncommon adverse effects include cardiac, muscular, and hematologic conditions7 (Table 4).

Table 3.

Risk Factors For Hydroxychloroquine-Induced Retinopathy.

Dose > 5 mg/kg (real weight)/da 
Duration of treatment > 5 y 
Cumulative dose > 1000 gb 
Kidney failurec 
Previous macular or retinal disease 
Concomitant tamoxifen 

Source: Fernandez1, Chew et al.2, Melles and Marmor6.

a

Doses > 5 mg entail a risk of retinopathy of 10% at 10 years and of approximately 40% at 20 years. Doses of 4-5 mg/kg/d involve a risk of < 2% after 10 years of therapy.

b

Cumulative doses of 1000 g are reached after 7 years of therapy with hydroxychloroquine 400 mg/d.

c

A 50% reduction in the glomerular filtration rate is associated with double the risk of retinal toxicity.

Table 4.

Potential Adverse Effects of Hydroxychloroquine.

Gastrointestinal  Anorexia, heartburn, diarrhea, and abdominal distension 
Ocular  Alteration of ocular accommodation (reversible) 
  Retinopathy (irreversible)a 
  Corneal opacities and corneal edema (reversible) 
Cutaneous  Skin rash, hyperpigmentation (reversible), and pruritus 
  Other infrequent effects include erythema multiforme, DRESS syndrome, Stevens-Johnson syndrome, TEN, AGEP,b photosensitivity 
Cardiac  Conduction alterations 
  Ventricular arrhythmia 
  Restrictive and obstructive heart disease 
  Congestive heart failure 
Muscular  Proximal myopathy 
Hematologic  Agranulocytosis, leukopenia, and anemia 
Hepatic  Hepatotoxicity 
Neuropsychiatric  Nightmares, irritability, mood alterations 

Abbreviations: AGEP, acute generalized exanthematous pustulosis; DRESS, drug reaction with eosinophilia and systemic symptoms; TEN, toxic epidermal necrolysis.

Source: Chew et al.2, Sardana et al.3.

a

The initial presentation of retinopathy is frequently asymptomatic or with paracentral, temporal, or pericentral scotoma.

b

Hydroxychloroquine is one of the main drugs involved in the development of AGEP, although this finding is infrequent.

Monitoring in Clinical Practice

An ophthalmological examination should be performed at baseline and annually after 5 years of therapy. A recent review did not report hemolysis during therapy with hydroxychloroquine in patients with a deficiency of the enzyme glucose-6-phosphate dehydrogenase; therefore, its routine assessment is not recommended7. Table 5 shows the main recommendations.

Table 5.

Hydroxychloroquine in Clinical Practice: Dose, Monitoring, and Precautions.

Dose  Most frequently used dose: 400 mg/d (≤ 5 mg/kg [real weight]/d) 
  In cases where therapy fails, plasma levels can be measured. Target level: > 750 ng/mLa 
Monitoring  Ophthalmology: 
  Baseline assessment during the first year of treatment and annually after the fifth yearb 
  Laboratory: 
  Complete blood count and biochemical profile including kidney function and liver values before initiation of treatmentc 
Precautions  Recommend stopping smoking (reduces the effect of antimalarial drugs) 
  Strict laboratory testing in patients with kidney failure 
  Cumulative doses (and the risk of retinopathy) can be decreased by discontinuing after 6-12 months in cutaneous lupus erythematosus or during periods of reduced risk (winter) 

Source: Fernandez1, Chew et al.2, Melles and Marmor6.

a

Plasma levels should be measured every 3 months, with 200-mg increases in dose until target values are reached. The dose can then be reduced to 400 mg/d, with good responses maintained in most cases.

b

Assessment should include campimetry and optical coherence tomography. This can be performed at shorter intervals in high-risk patients (Table 3). Ophthalmological screening does not prevent damage, but only makes it possible to detect retinopathy at early stages and thus prevent progression. Treatment should be discontinued if retinopathy is suspected.

c

No agreement on the need for regular checkups or on optimal intervals. Measurement of glucose-6-phosphate dehydrogenase levels is not necessary.

Hydroxychloroquine in Dermatologic DiseasesInflammatory and Autoimmune Skin DiseasesLupus erythematosus

Antimalarial drugs are first-line agents for the treatment of systemic lupus erythematosus (SLE). They reduce joint and skin symptoms, disease activity, target organ damage, and cardiovascular complications and increase survival8.

As for cutaneous lupus erythematosus (CLE), a recent systematic review of 10 studies and 852 patients revealed an effectiveness of 50% to 79% (50% in the 2 randomized clinical trials included)9 (Table 6). The degree of efficacy varied depending on the subtype of CLE and was greater for acute CLE than for subacute CLE and chronic CLE10. In the case of tumid lupus erythematosus, a retrospective study (n = 36) revealed satisfactory responses with hydroxychloroquine in 61% of cases9. Hydroxychloroquine seems to be effective in lupus panniculitis2. The time to clinical response is another factor that depends on the subtype of CLE; therefore, the effectiveness of hydroxychloroquine should be evaluated at 4 weeks in acute disease, 5 weeks in subacute disease, and 8 weeks in chronic disease10.

Table 6.

Main Clinical Studies on the Use of Hydroxychloroquine in Cutaneous Lupus Erythematosusa.

Author, year  Type of study  Objective  No. of patients  Main findings 
Ruzicka et al., 1992  Randomized clinical trial  Compare HCQ and acitretin  58 patients with CDCL y SACLE (28 treated with HCQ)  Favorable response in 50% of cases. Similar results for both drugs. Better safety profile with HCQ 
Chang et al., 2011  Prospective cohort study  Evaluate the effectiveness of antimalarial drugs  128 patients with CLE  Significant improvement in 55% of patients at 2 mo. Addition of quinacrine enabled nonresponders to achieve a good response in 67% of cases 
Wahie et al., 2011  Multicenter retrospective study  Evaluate the effectiveness of HCQ and the effect of genetic polymorphisms on clinical response  200 patients with CDCL  Response in 60% 
        Medication was suspended in 4% of cases owing to adverse effects 
        No differences in genetic metabolization profiles 
Frances et al., 2012  Prospective multicenter study  Study the relationship between blood concentrations of HCQ and clinical efficacy  300 patients with CCL or SACLE  Complete remission in 38%, partial remission in 29%, no response in 33% 
        Response improved with the increased plasma concentration of HCQ 
Alniemi et al., 2017  Retrospective study  Evaluate clinical characteristics, associated diseases, and outcomes of therapy  90 patients with SACLE (46 patients treated with HCQ)  Complete response in 74% of patients treated with HCQ 
Yokohama et al., 2017  Randomized clinical trial  Evaluate efficacy and tolerability of HCQ  103 patients with CLE  Higher percentage of improvement or marked improvement with HCQ than with placebo (51.4% vs 8.7%) (P = .0002) 
Ototake et al., 2019  Retrospective study  Study the efficacy of HCQ in various subtypes of CLE  35 patients with CLE  Favorable response in 87% (ACLE > SACLE > CCL). More rapid response in ACLE, slower response in CCL 

Abbreviations: ACLE, acute cutaneous lupus erythematosus; CCL, chronic cutaneous lupus; CDCL, chronic discoid cutaneous lupus; CLE, cutaneous lupus erythematosus; HCQ, hydroxychloroquine; SACLE, subacute cutaneous lupus erythematosus.

Source: Shipman et al.9, Ototake et al.10.

a

Studies with more than 30 patients were selected.

Various alternatives can be used for CLE that fails to respond to hydroxychloroquine. These include determining plasma levels of hydroxychloroquine. In SLE, therapeutic levels are between 500 and 1000 ng/mL. The optimal ranges for CLE have not yet been determined. Values lower than 200 ng/mL are associated with poor adherence. In refractory cases, increasing the dose to concentrations higher than 750 ng/mL has been associated with a significant improvement in symptoms1. Another option involves switching to chloroquine, which improves the skin condition in a significant percentage of patients, albeit with a poorer safety profile. Hydroxychloroquine can also be combined with quinacrine 100 mg/d2,3. This agent is not sold in Spain and must be obtained as a foreign medication.

Dermatomyositis

Treatment of the cutaneous manifestations of dermatomyositis can prove more difficult than that of the muscular manifestations. A retrospective multicenter study of 115 persons (93 with amyopathic dermatomyositis and 22 with hypomyopathic dermatomyositis) showed that antimalarial agents were the most frequently indicated treatment (76%), with skin involvement controlled in only 11%. Most patients needed immunosuppressants or immunoglobulins11. Similar results were recorded in a cohort study of 41 persons with amyopathic dermatomyositis12. A recent study revealed a significant increase in interferon β–producing myeloid dendritic cells in the skin of patients with dermatomyositis who had not responded to treatment with hydroxychloroquine. The increase in this cell subtype could account for the diminished response to antimalarial drugs13.

Some studies have reported that individuals with dermatomyositis may be more frequently affected by hydroxychloroquine-induced cutaneous adverse effects (around 10%) than patients with SLE14, although this has not been confirmed by other authors.

Morphea

A recent retrospective study (n = 84) reported a complete response rate that was greater than 40% and a partial response rate of around 50%. The median time to optimal clinical response was 12 months. Patients with plaque morphea responded better than those with generalized, linear, or deep forms15. Another retrospective study of 16 patients with eosinophilic fasciitis showed that 25% of patients who received hydroxychloroquine in monotherapy achieved a complete response and 50% a partial response. Hydroxychloroquine was a good alternative, although it was not superior to oral corticosteroids16.

Urticarial vasculitis

A retrospective multicenter study of 57 persons with hypocomplementemic urticarial vasculitis revealed that hydroxychloroquine was effective as a first-line treatment, with response rates similar to those of systemic corticosteroids and an overall response rate (complete + partial) of more than 50%, albeit with reduced efficacy in cases of recurrence and cases refractory to other drugs17. A recent systematic review on urticarial vasculitis concluded that hydroxychloroquine (400 mg/d) is potentially effective in this disease and enables corticosteroids to be tapered18.

Lichen planus

A retrospective study (n = 61) of patients with cutaneous lichen planus (54%), cutaneous and mucosal lichen planus (25%), or mucosal lichen planus (21%) revealed resolution of symptoms in 61% of patients treated with hydroxychloroquine 400 mg/d in a mean of 80 days19. Favorable responses have been reported in isolated cases of actinic lichen planus20.

In a series of 21 patients with oral erosive lichen planus treated with hydroxychloroquine 400 mg/d for 2 to 4 months, a complete response was recorded in 24% and at least moderate improvement in 57%21. A previous open-label clinical trial (n = 10) had found similar results.22 In a prospective study (n = 8), a significant clinical improvement was recorded in all patients with antimalarial drugs (7 with chloroquine 3.5-6 mg/kg/d and 1 with hydroxychloroquine 400 mg/d) after a mean of 2.4 months23. A retrospective study of patients with lichen planus of the vulva and vagina (n = 15) revealed a clinical response rate of 60% with a dose of hydroxychloroquine 200-800 mg/d (400 mg/d in most patients); median time to response was 5 months24.

Lichen planopilaris

A retrospective study of 23 patients with lichen planopilaris (n = 40) revealed a complete response with hydroxychloroquine in 61% of patients25. Another retrospective study reported diminished disease activity in 83% of cases after 12 months of treatment26. However, methotrexate proved superior to hydroxychloroquine for reducing disease activity in a randomized clinical trial (n = 29)27.

Frontal fibrosing alopecia

A recent review of the literature reported stabilization of frontal fibrosing alopecia in 71% of cases (41/58). The authors recommended hydroxychloroquine as second-line therapy after combination therapy with intralesional corticosteroids and topical minoxidil and tacrolimus28. A retrospective study of 36 patients with frontal fibrosing alopecia treated with various drugs (16 with hydroxychloroquine) revealed a response rate of 73% for hydroxychloroquine, although most were partial responses (64%)29. Similar results were reported in another retrospective study that included 11 patients with frontal fibrosing alopecia26. A large-scale retrospective multicenter study revealed stabilization of disease with hydroxychloroquine in 59% of cases (32/54) and improvement of symptoms in 15% (8/54)30.

Alopecia areata

A retrospective study of 9 children with refractory alopecia areata (7 with severe alopecia areata) revealed regrowth greater than 50% in 5 cases (2 patients reached an almost complete response after 1 year of therapy)31. However, no favorable responses were observed in a series of 8 adult patients2.

Chronic spontaneous urticaria

A randomized clinical trial including 48 patients with H1 antihistamine–refractory chronic spontaneous urticaria compared the combination of placebo and high doses of H1 antihistamines (4 tablets per day) with the combination of hydroxychloroquine and high-dose H1 antihistamines. In the hydroxychloroquine group, 28% achieved full remission compared with 0% in the control group (P = .01)32.

Granulomatous Skin DiseasesGranuloma annulare

A retrospective study of 18 patients, most of whom had generalized granuloma annulare showed that 55% improved with hydroxychloroquine33. Similar results were found in a prospective case series (n = 9)34. Favorable results have been reported in annular elastolytic giant-cell granuloma2.

Necrobiosis lipoidica

In a series of 8 patients treated with antimalarial agents (6 with chloroquine and 2 with hydroxychloroquine), an almost complete response was recorded in 4 patients and stabilization of symptoms in 335. Favorable findings have also been reported in isolated cases of ulcerative forms36.

Cutaneous sarcoidosis

An open-label clinical trial (n = 17) revealed that 71% of patients achieved a complete clinical response and 33% a partial response37. In a series of 3 cases, the lesions resolved in all 3 patients38. Complete remission with oral prednisone and hydroxychloroquine has also been reported with ulcerative cutaneous sarcoidosis39.

Photoinduced/Photoaggravated DermatosesPorphyria cutanea tarda

A randomized clinical trial (n = 48) found that low-dose hydroxychloroquine (100 mg twice weekly) was as effective and safe as phlebotomy in patients with porphyria cutanea tarda. The median time to clinical remission was 6.1 months40. Similar results were recorded in another trial (n = 40) in alcoholic patients with porphyria cutanea tarda41.

Polymorphic light eruption

A clinical trial including 117 patients with polymorphic light eruption showed that hydroxychloroquine (400 mg/d for 1 month followed by 200 mg/d for a further month) was superior to chloroquine for control of sunburn, pruritus, scaling, and erythema. The clinical response was good or excellent in 69% of patients and complete in 44%42. A previous clinical trial (n = 13) had shown moderate clinical responses with a significant reduction in erythema when used in summer (400 mg/d for 1 month followed by 200 mg/d for 2 months)43.

Actinic prurigo

Hydroxychloroquine is a safe and effective option in children with actinic prurigo at doses of 3-5 mg/kg (the dose can be reduced by half after a few months)44.

Rosacea

A clinical trial analyzing 66 patients with rosacea compared the effectiveness of hydroxychloroquine 400 mg/d with that of doxycycline 100 mg/d for 2 months; similar results were reported for both groups. The authors concluded that hydroxychloroquine could be effective in this disease and, therefore, could be used for the treatment of rosacea in pregnant women, for whom few alternative treatments are available45.

Other Dermatologic Diseases

Favorable responses to hydroxychloroquine have been reported in the treatment of diseases such as lichen sclerosus, reticular erythematous mucinosis, lipodermatosclerosis, chronic ulcerative stomatitis, chronic actinic dermatitis, solar urticaria2, Schnitzler syndrome, scleromyxedema, eosinophilic annular erythema, antiphospholipid syndrome, Kikuchi-Fujimoto disease1, pseudolymphoma3, Jessner lymphocytic infiltration of the skin, pemphigus foliaceus, interstitial granulomatous dermatitis, follicular mucinosis, and chronic erythema nodosum46 (Table 7).

Table 7.

Off-Label Use of Hydroxychloroquine in Dermatology and Type of Study Supporting it for Each Disease.

Disease  Study supporting use 
Dermatomyositis  Retrospective studies 
Morphea  Retrospective studies 
Granuloma annulare  Retrospective studies 
Necrobiosis lipoidica  Case series 
Cutaneous sarcoidosis  Open-label clinical trial 
Spontaneous chronic urticaria  Randomized clinical trial 
Urticarial vasculitis  Retrospective studies 
Lichen planus  Retrospective studies, open-label clinical trial 
Alopecia areata  Retrospective studies 
Porphyria cutanea tarda  Randomized clinical trials 
Polymorphic light eruption  Randomized clinical trials 
Rosacea  Randomized clinical trial 
Lichen sclerosus  Small case series or isolated cases 
Lipodermatosclerosis  Small case series or isolated cases 
Chronic actinic dermatitis  Small case series or isolated cases 
Actinic pruritus  Small case series or isolated cases 
Urticaria solar  Small case series or isolated cases 
Schnitzler syndrome  Small case series or isolated cases 
Scleromyxedema  Small case series or isolated cases 
Eosinophilic annular erythema  Small case series or isolated cases 
Antiphospholipid syndrome  Retrospective studies 
Kikuchi-Fujimoto disease  Small case series or isolated cases 
Pseudolymphoma  Small case series or isolated cases 
Chronic erythema nodosum  Small case series or isolated cases 

As we have seen, hydroxychloroquine is a polyvalent drug. It can be prescribed in many skin conditions, with favorable clinical outcomes. Its immunomodulatory—but not immunosuppressive—action and favorable safety profile make it suitable even for children and pregnant and breastfeeding women1. Given that a satisfactory clinical response generally takes several months, patients should be forewarned in order to avoid discontinuation.

Hydroxychloroquine and COVID-19

Hydroxychloroquine has potent antifungal, antibacterial, and antiviral properties. An antiviral effect has been reported against a series of viruses, including influenza A and B, hepatitis B and C, herpes simplex, chikungunya, dengue, Zika, and Ebola.

Hydroxychloroquine was considered one of the most promising drugs for the treatment of COVID-19. Its role as an antiviral agent is based on its potential ability to inhibit fusion of the virus with the host cell, block transport of the virus from the endosomes to the endolysosomes, and diminish the cytokine storm in severely ill patients3. Antimalarial drugs interfere with glycosylation of the angiotensin-converting enzyme receptor, which is used by SARS-CoV-2 to enter cells, thus reducing viral penetration. They also alkalinize endosomes and endocytic vesicles, thus altering endocytosis of the virus, and diminish release of proinflammatory cytokines by reducing antigen presentation (especially of self-antigens) and activation of CD4+ T lymphocytes. They also reduce intracellular signaling of toll-like receptors47,48.

Despite the absence of consistent evidence that hydroxychloroquine was effective for treatment or prevention of COVID-19 and the fact that the Infectious Diseases Society of America only recommended it within the setting of randomized clinical trials, this antimalarial agent was used in various hospital treatment protocols and even recommended to the general public4. The United States Food and Drug Administration warned about potential cardiovascular effects of the drug and then authorized it for use in patients hospitalized with COVID-19 (March 28, 2020). They subsequently withdrew this authorization (June 15, 2020)49. The high demand for the drug (which multiplied 80-fold in the USA) led to difficulties with administration and shortages5. Furthermore, India, one of the main producers of generic hydroxychloroquine, temporarily banned exportation of the drug, thus affecting the global supply chain4. In an international survey sent to members of the Systemic Lupus International Collaborating Clinics (29% European), 55% reported a shortage of supplies of hydroxychloroquine for patients with SLE during the pandemic50. Other authors reported anxiety and uncertainty among patients with SLE who could not access the drug8,51. Furthermore, a major impact on malaria control programs was observed5,52. We were unable to find original articles on the impact of the shortage on patients with dermatologic conditions, although we believe that if this had continued over time, then the impact would have been considerable.

As for the effectiveness of hydroxychloroquine in COVID-19, a recent meta-analysis of 14 studies (n = 12 455) found no significant differences in survival, improvement in symptoms at day 10, or seroconversion rate and reported a greater frequency of cardiovascular and gastrointestinal effects than in the control groups49. A recent Cochrane database review revealed no significant differences in the risk of death from COVID-19 (or in the need for mechanical ventilation) when hydroxychloroquine was prescribed, and the authors recommended not performing further randomized clinical trials with this drug for this disease53. Similarly, a recent randomized clinical trial (n = 2314) was unable to find a positive effect for hydroxychloroquine as prophylaxis in COVID-1954.

Hydroxychloroquine is a key drug for control of malaria and treatment of patients with specific rheumatologic and/or dermatologic conditions. We feel that it is important to recommend caution when prescribing this drug off-label for other conditions (including COVID-19) in order to ensure supply to those patients who need it.

Conclusions

Hydroxychloroquine is an essential element of the dermatologist’s therapeutic arsenal. It is indicated as first- or second-line therapy in many photoinduced and photoaggravated inflammatory and granulomatous skin diseases. Using hydroxychloroquine for the treatment and prevention of COVID-19 has proven unsatisfactory and led to supply difficulties. Greater caution is required when recommending large-scale, off-label prescription of hydroxychloroquine to ensure that patients who need this drug have access to it.

Conflicts of Interest

The authors declare that they have no conflicts of interest.

References
[1]
A.P. Fernandez.
Updated recommendations on the use of hydroxychloroquine in dermatologic practice.
J Am Acad Dermatol, 76 (2017), pp. 1176-1182
[2]
C.Y. Chew, A. Mar, M. Nikpour, A.M. Saracino.
Hydroxychloroquine in dermatology: new perspectives on an old drug.
Australas J Dermatol, 61 (2020), pp. e150-e157
[3]
K. Sardana, S. Sinha, S. Sachdeva.
Hydroxychloroquine in dermatology and beyond: recent update.
Indian Dermatol Online J, 11 (2020), pp. 453-464
[4]
S. Cox.
To dispense or not to dispense: lessons to be learnt from ethical challenges faced by pharmacists in the COVID-19 pandemic.
Dev World Bioeth, (2020),
[5]
S. Baral, A. Rao, J.O.T. Rwema, C. Lyons, M. Cevik, A.E. Kågesten, et al.
Competing health risks associated with the COVID-19 pandemic and response: a scoping review.
[6]
R.B. Melles, M.F. Marmor.
The risk of toxic retinopathy in patients on long-term hydroxychloroquine therapy.
JAMA Ophthalmol, 132 (2014), pp. 1453-1460
[7]
S. Mohammad, M.E.B. Clowse, A.M. Eudy, L.G. Criscione-Schreiber.
Examination of hydroxychloroquine use and hemolytic anemia in G6PDH-Deficient patients.
Arthritis Care Res (Hoboken), 70 (2018), pp. 481-485
[8]
C.A. Peschken.
Possible consequences of a shortage of hydroxychloroquine for patients with systemic lupus erythematosus amid the COVID-19 pandemic.
J Rheumatol, 47 (2020), pp. 787-790
[9]
W.D. Shipman, N.A. Vernice, M. Demetres, J.L. Jorizzo.
An update on the use of hydroxychloroquine in cutaneous lupus erythematosus: a systematic review.
J Am Acad Dermatol, 82 (2020), pp. 709-722
[10]
Y. Ototake, Y. Yamaguchi, M. Kanaoka, A. Akita, N. Ikeda, M. Aihara.
Varied responses to and efficacies of hydroxychloroquine treatment according to cutaneous lupus erythematosus subtypes in Japanese patients.
J Dermatol, 46 (2019), pp. 285-289
[11]
J. Pinard, A.N. Femia, M. Roman, A. Alsarheed, C. Joyce, J. Lin, et al.
Systemic treatment for clinically amyopathic dermatomyositis at 4 tertiary care centers.
JAMA Dermatol, 155 (2019), pp. 494-496
[12]
C.O. Anyanwu, P.B. Chansky, R. Feng, K. Carr, J. Okawa, V.P. Werth.
The systemic management of cutaneous dermatomyositis: results of a stepwise strategy.
Int J Womens Dermatol, 3 (2017), pp. 189-194
[13]
K.L. Chen, J. Patel, M. Zeidi, M. Wysocka, M.M. Bashir, B. Patel, et al.
Myeloid dendritic cells are major producers of interferon-β in dermatomyositis and may contribute to hydroxychloroquine refractoriness.
J Invest Dermatol, 141 (2021),
[14]
A.L. Akabane, G.P. Smith.
Adverse cutaneous reactions secondary to hydroxychloroquine in patients with dermatomyositis, lupus erythematosus, and lichen planopilaris.
J Am Acad Dermatol, 85 (2021), pp. 1046-1047
[15]
A.B. Kumar, E.K. Blixt, L.A. Drage, R.A. El-Azhary, D.A. Wetter.
Treatment of morphea with hydroxychloroquine: a retrospective review of 84 patients at Mayo Clinic, 1996-2013.
J Am Acad Dermatol, 80 (2019), pp. 1658-1663
[16]
S. Lakhanpal, W.W. Ginsburg, C.J. Michet, J.A. Doyle, S.B. Moore.
Eosinophilic fasciitis: clinical spectrum and therapeutic response in 52 cases.
Semin Arthritis Rheum, 17 (1988), pp. 221-231
[17]
M. Jachiet, B. Flageul, A. Deroux, A. le Quellec, F. Maurier, F. Cordoliani, et al.
The clinical spectrum and therapeutic management of hypocomplementemic urticarial vasculitis: data from a French nationwide study of fifty-seven patients.
Arthritis Rheumatol, 67 (2015), pp. 527-534
[18]
P. Kolkhir, M. Grakhova, H. Bonnekoh, K. Krause, M. Maurer.
Treatment of urticarial vasculitis: a systematic review.
J Allergy Clin Immunol, 143 (2019), pp. 458-466
[19]
K.M. Hunt, S. Klager, Y.J. Kwak, N. Sami.
Successful systemic treatment outcomes of lichen planus: a single-center retrospective review.
Dermatol Ther, (2021), pp. e14903
[20]
P. Ramírez, M. Feito, E. Sendagorta, M. González‐Beato, R.D. Lucas.
Childhood actinic lichen planus: successful treatment with antimalarials.
Australas J Dermatol, 53 (2012), pp. e10-e13
[21]
A. Yeshurun, R. Bergman, N. Bathish, Z. Khamaysi.
Hydroxychloroquine sulphate therapy of erosive oral lichen planus.
Australas J Dermatol, 60 (2019), pp. e109-e112
[22]
D. Eisen.
Hydroxychloroquine sulfate (Plaquenil) improves oral lichen planus: an open trial.
J Am Acad Dermatol, 28 (1993), pp. 609-612
[23]
N. Rivas-Tolosa, C. Requena, B. Llombart, R. Alcalá, C. Serra-Guillén, L. Calomarde, et al.
Antimalarial drugs for the treatment of oral erosive lichen planus.
Dermatology, 232 (2016), pp. 86-90
[24]
H.B. Vermeer, H. Rashid, M.D. Esajas, J.M. Oldhoff, B. Horváth.
The use of hydroxychloroquine as a systemic treatment in erosive lichen planus of the vulva and vagina.
Br J Dermatol, 185 (2021), pp. 201-203
[25]
E. Nic Dhonncha, C.C. Foley, T. Markham.
The role of hydroxychloroquine in the treatment of lichen planopilaris: a retrospective case series and review.
Dermatol Ther, 30 (2017),
[26]
C. Chiang, D. Sah, B.K. Cho, B.E. Ochoa, V.H. Price.
Hydroxychloroquine and lichen planopilaris: efficacy and introduction of Lichen Planopilaris Activity Index scoring system.
J Am Acad Dermatol, 62 (2010), pp. 387-392
[27]
F.F. Naeini, M. Saber, A. Asilian, S.M. Hosseini.
Clinical efficacy and safety of methotrexate versus hydroxychloroquine in preventing lichen planopilaris progress: a randomized clinical trial.
Int J Prev Med, 8 (2017), pp. 37
[28]
A. Ho, J. Shapiro.
Medical therapy for frontal fibrosing alopecia: a review and clinical approach.
J Am Acad Dermatol, 81 (2019), pp. 568-580
[29]
A. Samrao, A.-L. Chew, V. Price.
Frontal fibrosing alopecia: a clinical review of 36 patients.
Br J Dermatol, 163 (2010), pp. 1296-1300
[30]
S. Vañó-Galván, A.M. Molina-Ruiz, C. Serrano-Falcón, S. Arias-Santiago, A.R. Rodrigues-Barata, G. Garnacho-Saucedo, et al.
Frontal fibrosing alopecia: a multicenter review of 355 patients.
J Am Acad Dermatol, 70 (2014), pp. 670-678
[31]
D. Yun, N.B. Silverberg, S.L. Stein.
Alopecia areata treated with hydroxychloroquine: a retrospective study of nine pediatric cases.
Pediatr Dermatol, 35 (2018), pp. 361-365
[32]
T. Boonpiyathad, A. Sangasapaviliya.
Hydroxychloroquine in the treatment of anti-histamine refractory chronic spontaneous urticaria, randomized single-blinded placebo-controlled trial and an open label comparison study.
Eur Ann Allergy Clin Immunol, 49 (2017), pp. 220-224
[33]
S.K. Grewal, C. Rubin, M. Rosenbach.
Antimalarial therapy for granuloma annulare: Results of a retrospective analysis.
J Am Acad Dermatol, 76 (2017), pp. 765-767
[34]
C. Cannistraci, I. Lesnoni La Parola, M. Falchi, M. Picardo.
Treatment of generalized granuloma annulare with hydroxychloroquine.
Dermatology, 211 (2005), pp. 167-168
[35]
F. Durupt, S. Dalle, S. Debarbieux, B. Balme, S. Ronger, L. Thomas.
Successful treatment of necrobiosis lipoidica with antimalarial agents.
Arch Dermatol, 144 (2008), pp. 118-119
[36]
M. Kavala, S. Sudogan, I. Zindanci, E. Kocaturk, B. Can, Z. Turkoglu, et al.
Significant improvement in ulcerative necrobiosis lipoidica with hydroxychloroquine.
Int J Dermatol, 49 (2010), pp. 467-469
[37]
E. Jones, J.P. Callen.
Hydroxychloroquine is effective therapy for control of cutaneous sarcoidal granulomas.
J Am Acad Dermatol, 23 (1990), pp. 487-489
[38]
S. Modi, T. Rosen.
Micropapular cutaneous sarcoidosis: case series successfully managed with hydroxychloroquine sulfate.
Cutis, 81 (2008), pp. 351-354
[39]
E. Powell, T. Rosen.
Ulcerative sarcoidosis: a prototypical presentation and review.
Cutis, 100 (2017), pp. 312-316
[40]
A.K. Singal, C. Kormos-Hallberg, C. Lee, V.M. Sadagoparamanujam, J.J. Grady, D.H. Freeman, et al.
Low-dose hydroxychloroquine is as effective as phlebotomy in treatment of patients with porphyria cutanea tarda.
Clin Gastroenterol Hepatol, 10 (2012), pp. 1402-1409
[41]
L. Marchesi, C. di Padova, T. Cainelli, A. Reseghetti, F. Di Padova, P. Rovagnati, et al.
A comparative trial of desferrioxamine and hydroxychloroquine for treatment of porphyria cutanea tarda in alcoholic patients.
Photodermatology, 1 (1984), pp. 286-292
[42]
A. Pareek, U. Khopkar, S. Sacchidanand, N. Chandurkar, G.S. Naik.
Comparative study of efficacy and safety of hydroxychloroquine and chloroquine in polymorphic light eruption: a randomized, double-blind, multicentric study.
Indian J Dermatol Venereol Leprol, 74 (2008), pp. 18-22
[43]
G.M. Murphy, J.L. Hawk, I.A. Magnus.
Hydroxychloroquine in polymorphic light eruption: a controlled trial with drug and visual sensitivity monitoring.
Br J Dermatol, 116 (1987), pp. 379-386
[44]
M. Magaña-García.
Antimalarials for children.
J Am Acad Dermatol, 30 (1994), pp. 510
[45]
B. Wang, X. Yuan, X. Huang, Y. Tang, Z. Zhao, B. Yang, et al.
Efficacy and safety of hydroxychloroquine for treatment of patients with rosacea: a multicenter, randomized, double-blind, double-dummy, pilot study.
J Am Acad Dermatol, 84 (2021), pp. 543-545
[46]
P. Jarrett, M.J. Goodfield.
Hydroxychloroquine and chronic erythema nodosum.
Br J Dermatol, 134 (1996), pp. 373
[47]
M. Ortega-Peña, R. González-Cuevas.
Familiar dermatologic drugs as therapies for COVID-19.
Actas Dermosifiliogr, 112 (2021), pp. 118-126
[48]
J. Stojkovic-Filipovic, M. Bosic.
Treatment of COVID 19-Repurposing drugs commonly used in dermatology.
Dermatol Ther, 33 (2020), pp. e13829
[49]
A.H. Choudhuri, S. Duggal, B. Ahuja, P.S. Biswas.
The efficacy and safety of hydroxychloroquine (HCQ) in treatment of COVID19 — a systematic review and meta-analysis.
Indian J Med Microbiol, 39 (2021), pp. 159-170
[50]
A. Mendel, S. Bernatsky, A. Askanase, S.-C. Bae, A.E. Clarke, N. Costedoat-Chalumeau, et al.
Hydroxychloroquine shortages among patients with systemic lupus erythematosus during the COVID-19 pandemic: experience of the Systemic Lupus International Collaborating Clinics.
[51]
M. Shah, M. Sachdeva, R.P. Dodiuk-Gad.
The impact of hydroxychloroquine shortages on patients with dermatological conditions during COVID-19 pandemic.
Dermatol Ther, 33 (2020), pp. e13524
[52]
P.M. Abena, E.H. Decloedt, E. Bottieau, F. Suleman, P. Adejumo, N.A. Sam-Agudu, et al.
Chloroquine and hydroxychloroquine for the prevention or treatment of novel coronavirus disease (COVID-19) in Africa: caution for inappropriate off-label use in healthcare settings.
Am J Trop Med Hyg, 102 (2020), pp. 1184-1188
[53]
B. Singh, H. Ryan, T. Kredo, M. Chaplin, T. Fletcher.
Chloroquine or hydroxychloroquine for prevention and treatment of COVID-19.
Cochrane Database Syst Rev, 2 (2021), pp. CD013587
[54]
O. Mitjà, M. Corbacho-Monné, M. Ubals, A. Alemany, C. Suñer, C. Tebé, et al.
A cluster-randomized trial of hydroxychloroquine for prevention of Covid-19.
N Engl J Med, 384 (2021), pp. 417-427

Please cite this article as: Morgado-Carrasco D, Ibaceta-Ayala J, Piquero-Casals J. La hidroxicloroquina como fármaco fundamental en dermatología y su papel controvertido en la COVID-19. Actas Dermosifiliogr. 2022;113:166–175.

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