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Original Investigation |

Hydroxychloroquine-Induced Pigmentation in Patients With Systemic Lupus Erythematosus A Case-Control Study FREE

Moez Jallouli, MD1; Camille Francès, MD2,3; Jean-Charles Piette, MD1; Du Le Thi Huong, MD1; Philippe Moguelet, MD4; Cecile Factor, PhD5; Noël Zahr, PhD6; Makoto Miyara, MD, PhD1; David Saadoun, MD, PhD1; Alexis Mathian, MD, PhD1; Julien Haroche, MD, PhD1; Christian De Gennes, MD1; Gaelle Leroux, MD1; Catherine Chapelon, MD1; Bertrand Wechsler, MD1; Patrice Cacoub, MD1; Zahir Amoura, MD1; Nathalie Costedoat-Chalumeau, MD, PhD1 ; for the PLUS (Plaquenil LUpus Systemic) Study Group
[+] Author Affiliations
1Service de Médecine Interne, Centre de Référence National pour le Lupus Systémique et le Syndrome des Antiphospholipides, Université Paris 6, Assistance Publique–Hôpitaux de Paris (AP-HP), Paris, France
2Université Pierre et Marie Curie (UPMC), Université Paris 6, Paris, France
3Service de Dermatologie Allergologie, Hôpital Tenon, AP-HP, Paris, France
4Service d’Anatomopathologie, Hôpital Tenon, AP-HP, Paris, France
5Research Division, Guerbet, Aulnay sous Bois, France
6Service de Pharmacologie, Université Paris 6, AP-HP, Paris, France
JAMA Dermatol. 2013;149(8):935-940. doi:10.1001/jamadermatol.2013.709.
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Published online

Importance  Hydroxychloroquine-induced pigmentation is not a rare adverse effect. Our data support the hypothesis that hydroxychloroquine-induced pigmentation is secondary to ecchymosis or bruising.

Objective  To describe the clinical features and outcome of hydroxychloroquine (HCQ)-induced pigmentation in patients with systemic lupus erythematosus (SLE).

Design, Setting, and Participants  In a case-control study conducted at a French referral center for SLE and antiphospholipid syndrome, 24 patients with SLE, with a diagnosis of HCQ-induced pigmentation, were compared with 517 SLE controls treated with HCQ.

Main Outcomes and Measures  The primary outcome was the clinical features of HCQ-induced pigmentation. Skin biopsies were performed on 5 patients, both in healthy skin and in the pigmented lesions. The statistical associations of HCQ-induced pigmentation with several variables were calculated using univariate and multivariate analyses.

Results  Among the 24 patients, skin pigmentation appeared after a median HCQ treatment duration of 6.1 years (range, 3 months–22 years). Twenty-two patients (92%) reported that the appearance of pigmented lesions was preceded by the occurrence of ecchymotic areas, which gave way to a localized blue-gray or brown pigmentation that persisted. Twenty-three patients (96%) had at least 1 condition predisposing them to easy bruising. Results from skin biopsies performed on 5 patients showed that the median concentration of iron was significantly higher in biopsy specimens of pigmented lesions compared with normal skin (4115 vs 413 nmol/g; P < .001). Using multivariate logistic regression, we found that HCQ-induced pigmentation was independently associated with previous treatment with oral anticoagulants and/or antiplatelet agents and with higher blood HCQ concentration.

Conclusions and Relevance  Hydroxychloroquine-induced pigmentation is not a rare adverse effect of HCQ. Our data support the hypothesis that HCQ-induced pigmentation is secondary to ecchymosis or bruising.

Figures in this Article

Use of antimalarials (ie, quinacrine, chloroquine, hydroxychloroquine [HCQ]) can induce tissue pigmentation in a variety of organs, including skin, joint tissue, trachea, and cartilage in the nose and ears. In patients with systemic lupus erythematosus (SLE) treated with antimalarials, the incidence of cutaneous hyperpigmentation has been reported to run as high as 10% to 25%,1,2 with the majority of reported cases involving chloroquine treatment.1 To our knowledge, only 13 cases of pigmentation attributed to HCQ have been reported in the literature.1,312

The aim of this study was to describe the clinical features and outcome of HCQ-induced pigmentation in 24 patients with SLE. To analyze the risk factors for toxic effects, we performed a case-control study comparing these 24 patients with SLE with 517 patients with SLE in the PLUS (Plaquenil LUpus Systemic) Study who were treated with HCQ and did not have HCQ-induced pigmentation (PLUS Study: clinicaltrials.gov Identifier: NCT00413361).

Patients

This was a retrospective, monocentric (SLE clinic, Pitié-Salpêtrière, Paris) case-control study of patients with SLE with a diagnosis of HCQ-induced pigmentation. All patients gave their informed consent, and the study protocol was approved by a French ethics committee.

The inclusion criteria were patients with SLE diagnosed according to the American College of Rheumatology classification criteria,13 who had been treated with HCQ and had a diagnosis of HCQ-induced pigmentation. This diagnosis was made if the patient had typical pigmentation that was otherwise unexplained (pigmentation induced by toxins or other drugs, dermatoses, endocrinopathies, or nutritional conditions were then ruled out). An experienced dermatologist (C.F.) confirmed the diagnosis in all cases, either by seeing the patients (n = 9) or from pictures of the patients (n = 15).

Exclusion criteria were a previous treatment with chloroquine for more than 3 months (patients with short treatment for travel indications were not excluded) because chloroquine is usually considered more toxic than HCQ and most patients with SLE are now treated with HCQ only.

Clinical Data

For each patient, we collected data about sex, age at diagnosis of SLE, clinical and laboratory manifestations of the disease, and treatment history of SLE. All patients were interviewed to specify the date, circumstances of initial appearance, and evolution of HCQ-induced pigmentation lesions.

Skin Biopsies

Skin biopsies were performed on 5 patients in both healthy skin and pigmented lesions. After excision of each biopsy, one piece was analyzed using routine pathologic procedures; another piece was frozen at −80°C until preparation for testing. The tissues (10-40 mg) were then mineralized in 300 µL of nitric acid for 8 hours at 80°C (nitric acid 65% [Suprapur; Merck]) and then diluted 20 times with a scandium solution in reverse osmosis water (Milli-Q; Millipore Corporation). Total iron levels in skin were measured by inductively coupled plasma mass spectrometry on an ELAN DRC Plus (PerkinElmer Life and Analytical Sciences Inc). The results were expressed in nanomoles per gram of skin.

Control Group

We used patients included in the PLUS Study as a control group. The PLUS Study was a randomized, double-blind, placebo-controlled, multicenter trial to evaluate the interest of HCQ dose adaptation to its blood concentration.14 We included 573 patients with SLE treated with HCQ for at least 6 months. Patients with HCQ-induced pigmentation (n = 41) or for whom this specific data was unknown (n = 15) were excluded from the analysis, yielding a final control group of 517 patients.

Data Analysis

We compared both groups for clinical and biological data including SLE criteria, smoking status, weight, height, calculated ideal weight, creatinine level, and whole blood HCQ concentration. The HCQ concentration was determined as previously described.15 When several determinations of HCQ concentration were available for 1 patient, we provided the median concentration with the ranges and used the median in the analyses.

Statistical Analysis

The χ2 and Fisher exact tests were applied to analyze qualitative differences. The t test was used for comparison of quantitative parameters. Values of quantitative variables are expressed as mean (standard deviation). Statistical significance was established at P < .05. When several independent variables appeared significant in the univariate analysis, a logistic regression test was performed for multivariate analysis to rule out possible confounding variables. Odds ratios (ORs) were calculated to assess the risk of each variable. The statistical analysis was performed with SPSS software (SPSS Inc).

Description of Patients With HCQ-Induced Pigmentation

We found 24 patients with HCQ-induced pigmentation (23 women and 1 man). Thirteen patients (54%) were white, 5 (21%) were black, 4 (17%) were North African, and 2 (8%) were classified as “other.” In addition to HCQ, all patients had been treated with steroids, 6 (25%) with cyclophosphamide, 3 (13%) with methotrexate, 3 (13%) with thalidomide, and 2 (8%) with antiepileptic drugs. The main characteristics of the patients are summarized in Table 1.

Table Graphic Jump LocationTable 1.  Characteristics of Patients With SLE and Risk Factors of Hydroxychloroquine Toxic Effects in the HCQ-Induced Pigmentation Group Compared With Controls

Skin pigmentation appeared after a median duration of HCQ treatment of 6.1 years (range, 3 months–22 years) with a median cumulative dose of 720 g of HCQ (range, 36-3168 g).

Hyperpigmentation was localized on the anterior side of the legs in all patients, on the arms in 5, and on the palate in 1. Twenty-two patients (92%) reported that the appearance of pigmented lesions was preceded by the occurrence of ecchymotic areas, which gave way to a localized bluish-green or brown pigmentation that persisted for an unusually long time (Figure 1). They qualified the onset as “bruises that did not disappear.”

Place holder to copy figure label and caption
Figure 1.
Patient Photographs

A, Bluish-green pigmentation on the legs in a patient with systemic lupus erythematosus without lupus lesions at the time of the skin biopsy. B, Brown pigmentation on the legs in another patient who had systemic lupus erythematosus associated with diffuse discoid lupus. The skin biopsy was performed on the brown area distant from discoid lesions.

Graphic Jump Location

At the onset of the pigmented lesions, 23 patients (96%) had at least 1 condition predisposing them to easy bruising: 14 patients were treated with platelet antiaggregants and 9 with oral anticoagulants, 1 patient had persistent thrombocytopenia, and 4 patients recalled a previous severe trauma to their legs (the result of an unintentional injury in 3 cases and a contact sport injury in 1 case).

One patient also presented HCQ retinopathy that occurred prior to the skin pigmentation anomaly. Another patient developed an atrioventricular block of the first degree that was reversible after discontinuation of HCQ treatment.

Treatment with HCQ was discontinued definitively because of skin pigmentation in 2 patients who reported a gradual incomplete fading of hyperpigmentation. Among patients who continued HCQ treatment (n = 22), an improvement in pigmented lesions was reported in 6, despite the maintenance of a similar daily dose of HCQ. Pigmentation remained stable in the other patients.

During follow-up, 22 patients had measurements of blood HCQ concentration. The median number of measurements per patient was 3 (range, 1-11). The median HCQ concentration was 1190 ng/mL (range, 465-2229 ng/mL).

Skin Biopsies

Hematoxylin-eosin–stained biopsy specimens showed brown pigmented granules throughout the dermis and hypodermis in interstitial and perivascular macrophages and fibroblasts (Figure 2A). Perls staining was strongly positive, suggesting the presence of iron (Figure 2B). A Fontana-Masson stain highlighted some of these granules, also supporting the presence of melanin in the same areas. Increased melanin in the epidermal layer was also visible (Figure 2C).

Place holder to copy figure label and caption
Figure 2.
Histologic Analysis of Biopsy Specimens

A, Interstitial and perivascular brown pigmented granules in the dermis (hematoxylin-eosin-safran staining, original magnification ×100). B, Presence of iron in the same areas of the dermis (Perls staining, original magnification ×100). C, Presence of melanin with similar distribution and increased in epidermal basal layer (Fontana-Masson staining, original magnification ×400).

Graphic Jump Location

In 5 patients we measured the concentration of iron in skin specimens from healthy skin as well as pigmented lesions. The median concentrations of iron were significantly higher in the pigmented lesions compared with normal skin (4115 [range, 4025-5723] nmol/g vs 413 [165-775] nmol/g, respectively; P < .001) (Table 2).

Table Graphic Jump LocationTable 2.  Concentrations of Iron in Skin Biopsy Specimens From Healthy Skin and Pigmented Lesions
Comparisons of Characteristics of Cases and Controls

The characteristics of both groups are summarized in Table 1. We did not find significant differences between the 2 groups in terms of sex, SLE characteristics, SLE treatments (steroids and/or immunosuppressive drugs), median duration of HCQ therapy, or median cumulative dose of HCQ. Patients with HCQ-induced pigmentation had a higher frequency of associated antiphospholipid syndrome (8 patients [33%] vs 84 control patients [16%]; P = .046) and were more frequently treated with oral anticoagulants (9 patients [38%] vs 67 control patients [13%]; P = .003) or antiplatelet agents (14 patients [58%] vs 164 control patients [32%]; P = .007).

Measurements of blood HCQ concentration were available for 22 patients with HCQ-induced pigmentation and for all controls by definition. The median blood HCQ concentration was significantly higher in patients with HCQ-induced pigmentation than in controls (1190 vs 841 ng/mL, respectively; P = .008). We then compared the median blood HCQ concentration between patients included in PLUS Study with HCQ-induced pigmentation (n = 41) and without (ie, the control group, n = 571). The difference was not significant (947 vs 841 ng/mL, respectively; P = .19).

Using multivariate logistic regression, we found that HCQ-induced pigmentation was independently associated with treatment with oral anticoagulants (OR, 6.77; 95% CI, 1.59-28.71) (P = .009) and/or antiplatelet agents (OR, 3.54; 95% CI, 1.42-8.81) (P = .006) and with number of patients with a HCQ concentration higher than 1000 ng/mL (OR, 2.8; 95% CI, 1.12-6.96) (P = .03).

To our knowledge, only 13 cases of HCQ-induced pigmentation have been reported in the literature.1,312 In this case-control study, we describe a series of 24 SLE patients with HCQ-induced pigmentation and compare them with a large control group. The incidence of HCQ-induced pigmentation is unknown. We can only extrapolate it from the data of the PLUS Study, in which we included 573 patients with SLE treated with HCQ for at least 6 months. Among patients in whom the “HCQ-induced pigmentation” item was assessed by the investigators (n = 558), 41 (7%) presented this adverse effect. Given that patients with HCQ-induced pigmentation may sometimes stop HCQ treatment for aesthetic reasons—when informed of the relationship—or because of an associated toxic effect, this rate may be slightly underestimated.

Skin pigmentation related to antimalarials is described as yellow brown to slate gray or black pigmentation, which predominates on the anterior side of the shins but can also be seen in the face, forearms, mouth mucosa (essentially hard palace and gingivae) and nail beds.16 This is consistent with our findings because all patients had skin pigmentation lesions on the anterior side of their legs.

Antimalarial drug-induced pigmentation has been suggested as a marker for patients at risk of ocular adverse effects.16 Among 24 patients, only 1 patient had HCQ-related retinal toxic effects. We were unable to compare this frequency to the PLUS Study patients because retinopathy was an exclusion criterion in the PLUS Study.

Hydroxychloroquine-induced pigmentation lesions usually begin after a few months or years of treatment. When we compared our patients with the controls, we found no significant association with the duration of HCQ treatment or with the cumulative dose of HCQ. Interestingly, 4 patients (17%) developed this adverse effect during the first year of treatment and 10 (42%) before the fifth year. These results argue that, unlike HCQ retinopathy,17 HCQ treatment duration and cumulative HCQ dose are not major risk factors for pigmented lesions.

At the onset of pigmented lesions, 23 patients (96%) had at least 1 condition predisposing them to easy bruising, essentially treatment with oral anticoagulants and/or antiplatelet agents, which were also found to be independently associated with HCQ-induced pigmentation in the multivariate logistic regression. Moreover, all patients had been previously treated with steroids, which can also facilitate bruising, but this variable was not statistically different from the control group. Few histological studies have been performed in patients with antimalarial-induced pigmentation,1,11,12,18 and the majority of reports do not specify which antimalarial treatment was used.12,18 Similar to our results, melanin granules and hemosiderin deposits were generally observed within the dermis,11,12,18 which was consistent with ecchymotic areas. These findings led us to measure for the first time the concentration of iron in skin biopsy specimens from 5 patients, taken from both healthy skin and from pigmented lesions. The median concentration of iron was 10-fold higher in the pigmented lesions than in normal skin. This result supports the hypothesis that this coloration is first induced by bruising and is concordant with the report by 22 patients regarding its initiation as “bruises that did not disappear.” As in hemochromatosis, a high content of hemosiderin might induce increased activation of melanocytes.19 Interestingly, the occurrence of HCQ-induced pigmentation lesions at sites of previous trauma has also been observed in 1 subtype of minocycline-induced pigmentation.20 Similarly to minocycline-induced pigmentation that has distinct morphologic characterization and mechanisms, trauma may not be the only mechanism of HCQ-induced pigmentation. This is emphasized by the fact that hyperpigmentation can be rarely localized on the palate and the nails. The mechanism involved in such cases is unknown.

Blood HCQ concentration can be measured by high-performance liquid chromatography in whole blood. It has been previously demonstrated that blood HCQ concentration is a marker and predictor for SLE flares.15 Regarding the link between blood HCQ concentration and HCQ toxicity, we only know that high blood HCQ concentrations were positively associated with an increased risk of adverse gastrointestinal reactions in a study published by Munster et al.21 In our study, blood HCQ concentrations were significantly higher in HCQ-induced pigmentation cases than in controls. This result is interesting from a physiopathological point of view. However, given the small differences between cases and controls and the lack of difference of blood HCQ concentrations between the PLUS Study patients with and without HCQ-induced pigmentation and given the wide range of distribution in blood HCQ concentrations, this result is probably not relevant for predicting the risk of HCQ-induced pigmentation in clinical practice.

The limitations of our study are mainly due to its retrospective nature. Although we showed that HCQ-induced pigmentation is not rare, the relatively long delay of onset of these pigmented lesions (6.1 years; range, 3 months–22 years) makes a prospective study unlikely to be performed. To overcome the retrospective nature of our study, an experienced dermatologist (C.F.) confirmed the diagnosis in all cases.

In conclusion, HCQ-induced pigmentation is not a rare adverse effect of HCQ, with a minimal incidence estimated at 7.3%. Its localization and association with factors facilitating bruising, interviews with patients, and data from skin biopsies support the hypothesis that HCQ-induced pigmentation is secondary to ecchymosis or bruising.

Corresponding Author: Nathalie Costedoat-Chalumeau, MD, PhD, Faculté Paris 6, Hôpital Pitié-Salpêtrière, Service de Médecine Interne, 47-83 Boulevard de l’Hôpital, 75013 Paris, France (nathalie.costedoat@gmail.com).

Accepted for Publication: January 30, 2013.

Published Online: July 3, 2013. doi:10.1001/jamadermatol.2013.709.

Author Contributions: All authors had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Drs Jallouli and Francès contributed equally to this work.

Study concept and design: Francès, Piette, Costedoat-Chalumeau.

Acquisition of data: Jallouli, Francès, Piette, Le Thi Huong, Moguelet, Factor, Zahr, Saadoun, Mathian, Haroche, De Gennes, Leroux, Chapelon, Wechsler, Cacoub, Amoura, Costedoat-Chalumeau.

Analysis and interpretation of data: Jallouli, Francès, Piette, Miyara, Amoura, Costedoat-Chalumeau.

Drafting of the manuscript: Jallouli, Zahr, Wechsler, Amoura, Costedoat-Chalumeau.

Critical revision of the manuscript for important intellectual content: Jallouli, Francès, Piette, Le Thi Huong, Moguelet, Factor, Miyara, Saadoun, Mathian, Haroche, De Gennes, Leroux, Chapelon, Cacoub, Amoura, Costedoat-Chalumeau.

Statistical analysis: Jallouli.

Administrative, technical, and material support: Francès, Piette, Zahr, Le Thi Huong, Moguelet, Factor, Miyara, Saadoun, Haroche, Leroux, Chapelon, Amoura, Costedoat-Chalumeau.

Study supervision: Francès, Piette, Wechsler, Cacoub, Costedoat-Chalumeau.

Conflict of Interest Disclosures: None reported.

Funding/Support: The PLUS Study (control group) was supported in part by the French Programme Hospitalier de Recherche Clinique (PHRC) 2005 Ministère de la Santé, the Département de la Recherche Clinique et du Développement, and Sanofi.

Role of the Sponsors: The French PHRC 2005 Ministère de la Santé and the Département de la Recherche Clinique et du Développement provided logistic and administrative support for the PLUS Study. Sanofi provided the hydroxychloroquine and placebo tablets for the PLUS Study. The company had no role in the initiation, planning, conduct, data assembly, analysis, or interpretation of the study.

Group Information: The PLUS Study collaborators include Felix Ackermann, Bouchra Asli, Leonardo Astudillo, Olivier Aumaître, Cristina Belizna, Nadia Belmatoug, Olivier Benveniste, Audrey Benyamine, Holly Bezanahary, Patrick Blanco, Olivier Bletry, Bahram Bodaghi, Pierre Bourgeois, Benoît Brihaye, Emmanuel Chatelus, Judith Cohen-Bittan, Richard Damade, Eric Daugas, Jean-François Delfraissy, Céline Delluc, Aurélien Delluc, Hélène Desmurs-Clavel, Pierre Duhaut, Alain Dupuy, Isabelle Durieu, Hang-Korng Ea, Olivier Fain, Dominique Farge, Christian Funck-Brentano, Lionel Galicier, Frédérique Gandjbakhch, Justine Gellen-Dautremer, Pascale Ghillani-Dalbin, Bertrand Godeau, Cécile Goujard, Catherine Grandpeix, Claire Grange, Lamiae Grimaldi, Gaëlle Guettrot, Loïc Guillevin, Eric Hachulla, Jean-Robert Harle, Pierre Hausfater, Jean-Sébastien Hulot, Jean Jouquan, Jean-Emmanuel Kahn, Gilles Kaplanski, Homa Keshtmand, Mehdi Khellaf, Olivier Lambotte, David Launay, Philippe Lechat, Véronique Le Guern, Hervé Levesque, Olivier Lidove, Nicolas Limal, Frédéric Lioté, Eric Liozon, Kim Ly, Matthieu Mahevas, Kubéraka Mariampillai, Xavier Mariette, Karin Mazodier, Marc Michel, Nathalie Morel, Luc Mouthon, Lucile Musset, Jacques Ninet, Eric Oksenhendler, Thomas Papo, Jean-Luc Pellegrin, Laurent Perard, Olivier Peyr, Anne-Marie Piette, Vincent Poindron, Jacques Pourrat, Fabienne Roux, Sabrinel Sahali, Bernadette Saint-Marcoux, Françoise Sarrot-Reynauld, Laurent Sailler, Karim Sacre, Yoland Schoindre, Jérémie Sellam, Damien Sene, Jacques Serratrice, Pascal Seve, Jean Sibilia, Claude Simon, Amar Smail, Christelle Sordet, Jérome Stirnemann, Benjamin Terrier, Salim Trad, Jean-François Viallard, Elisabeth Vidal, Pierre-Jean Weiller.

Additional Contributions: We thank the patients, the Association France Lupus (AFL) for a grant for the PLUS Study, the Clinical Research Unit of Pitié-Salpêtrière Hospital, which dealt with the methodological aspects, data management and monitoring, and the sponsor of the PLUS Study, Assistance Publique–Hôpitaux de Paris.

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Figures

Place holder to copy figure label and caption
Figure 1.
Patient Photographs

A, Bluish-green pigmentation on the legs in a patient with systemic lupus erythematosus without lupus lesions at the time of the skin biopsy. B, Brown pigmentation on the legs in another patient who had systemic lupus erythematosus associated with diffuse discoid lupus. The skin biopsy was performed on the brown area distant from discoid lesions.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 2.
Histologic Analysis of Biopsy Specimens

A, Interstitial and perivascular brown pigmented granules in the dermis (hematoxylin-eosin-safran staining, original magnification ×100). B, Presence of iron in the same areas of the dermis (Perls staining, original magnification ×100). C, Presence of melanin with similar distribution and increased in epidermal basal layer (Fontana-Masson staining, original magnification ×400).

Graphic Jump Location

Tables

Table Graphic Jump LocationTable 1.  Characteristics of Patients With SLE and Risk Factors of Hydroxychloroquine Toxic Effects in the HCQ-Induced Pigmentation Group Compared With Controls
Table Graphic Jump LocationTable 2.  Concentrations of Iron in Skin Biopsy Specimens From Healthy Skin and Pigmented Lesions

References

Puri  PK, Lountzis  NI, Tyler  W, Ferringer  T.  Hydroxychloroquine-induced hyperpigmentation: the staining pattern. J Cutan Pathol. 2008;35(12):1134-1137.
PubMed   |  Link to Article
Hendrix  JD  Jr, Greer  KE.  Cutaneous hyperpigmentation caused by systemic drugs. Int J Dermatol. 1992;31(7):458-466.
PubMed   |  Link to Article
Veraldi  S, Schianchi-Veraldi  R, Scarabelli  G.  Pigmentation of the gums following hydroxychloroquine therapy. Cutis. 1992;49(4):281-282.
PubMed
Millard  TP, Kirk  A, Ratnavel  R.  Cutaneous hyperpigmentation during therapy with hydroxychloroquine. Clin Exp Dermatol. 2004;29(1):92-93.
PubMed   |  Link to Article
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