<?xml version="1.0" encoding="UTF-8" standalone="no"?>
<!DOCTYPE article PUBLIC "-//NLM//DTD Journal Publishing DTD v2.3 20070202//EN" "journalpublishing.dtd">
<article xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" article-type="case-report" dtd-version="2.3" xml:lang="EN">
<front>
<journal-meta>
<journal-id journal-id-type="publisher-id">Front. Immunol.</journal-id>
<journal-title>Frontiers in Immunology</journal-title>
<abbrev-journal-title abbrev-type="pubmed">Front. Immunol.</abbrev-journal-title>
<issn pub-type="epub">1664-3224</issn>
<publisher>
<publisher-name>Frontiers Media S.A.</publisher-name>
</publisher>
</journal-meta>
<article-meta>
<article-id pub-id-type="doi">10.3389/fimmu.2024.1383343</article-id>
<article-categories>
<subj-group subj-group-type="heading">
<subject>Immunology</subject>
<subj-group>
<subject>Case Report</subject>
</subj-group>
</subj-group>
</article-categories>
<title-group>
<article-title>Hydroxychloroquine-induced hyperpigmentation of the skin and bull&#x2019;s-eye maculopathy in rheumatic patients: a case report and literature review</article-title>
</title-group>
<contrib-group>
<contrib contrib-type="author">
<name>
<surname>Peng</surname>
<given-names>Ji-peng</given-names>
</name>
<xref ref-type="aff" rid="aff1">
<sup>1</sup>
</xref>
<uri xlink:href="https://loop.frontiersin.org/people/2650919"/>
<role content-type="https://credit.niso.org/contributor-roles/writing-original-draft/"/>
<role content-type="https://credit.niso.org/contributor-roles/writing-review-editing/"/>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Yang</surname>
<given-names>Xiao-yu</given-names>
</name>
<xref ref-type="aff" rid="aff1">
<sup>1</sup>
</xref>
<role content-type="https://credit.niso.org/contributor-roles/writing-original-draft/"/>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Luo</surname>
<given-names>Feng</given-names>
</name>
<xref ref-type="aff" rid="aff1">
<sup>1</sup>
</xref>
<xref ref-type="aff" rid="aff2">
<sup>2</sup>
</xref>
<role content-type="https://credit.niso.org/contributor-roles/writing-original-draft/"/>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Yuan</surname>
<given-names>Xue-mei</given-names>
</name>
<xref ref-type="aff" rid="aff1">
<sup>1</sup>
</xref>
<xref ref-type="aff" rid="aff2">
<sup>2</sup>
</xref>
<role content-type="https://credit.niso.org/contributor-roles/writing-original-draft/"/>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Xiong</surname>
<given-names>Hong</given-names>
</name>
<xref ref-type="aff" rid="aff1">
<sup>1</sup>
</xref>
<role content-type="https://credit.niso.org/contributor-roles/writing-original-draft/"/>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Ma</surname>
<given-names>Wu-kai</given-names>
</name>
<xref ref-type="aff" rid="aff1">
<sup>1</sup>
</xref>
<xref ref-type="aff" rid="aff2">
<sup>2</sup>
</xref>
<uri xlink:href="https://loop.frontiersin.org/people/1354533"/>
<role content-type="https://credit.niso.org/contributor-roles/writing-original-draft/"/>
</contrib>
<contrib contrib-type="author" corresp="yes">
<name>
<surname>Yao</surname>
<given-names>Xue-ming</given-names>
</name>
<xref ref-type="aff" rid="aff1">
<sup>1</sup>
</xref>
<xref ref-type="aff" rid="aff2">
<sup>2</sup>
</xref>
<xref ref-type="author-notes" rid="fn001">
<sup>*</sup>
</xref>
<role content-type="https://credit.niso.org/contributor-roles/writing-original-draft/"/>
<role content-type="https://credit.niso.org/contributor-roles/writing-review-editing/"/>
</contrib>
</contrib-group>
<aff id="aff1">
<sup>1</sup>
<institution>Guizhou University of Traditional Chinese Medicine</institution>, <addr-line>Guiyang</addr-line>, <country>China</country>
</aff>
<aff id="aff2">
<sup>2</sup>
<institution>Department of Rheumatology and Immunology, Second Affiliated Hospital of Guizhou University of Traditional Chinese Medicine</institution>, <addr-line>Guiyang</addr-line>, <country>China</country>
</aff>
<author-notes>
<fn fn-type="edited-by">
<p>Edited by: Chris Wincup, King&#x2019;s College Hospital NHS Foundation Trust, United Kingdom</p>
</fn>
<fn fn-type="edited-by">
<p>Reviewed by: Seyed Parsa Eftekhar, Babol University of Medical Sciences, Iran</p>
<p>Francesco Puppo, University of Genoa, Italy</p>
</fn>
<fn fn-type="corresp" id="fn001">
<p>*Correspondence: Xue-ming Yao, <email xlink:href="mailto:yxming19@foxmail.com">yxming19@foxmail.com</email>
</p>
</fn>
</author-notes>
<pub-date pub-type="epub">
<day>10</day>
<month>04</month>
<year>2024</year>
</pub-date>
<pub-date pub-type="collection">
<year>2024</year>
</pub-date>
<volume>15</volume>
<elocation-id>1383343</elocation-id>
<history>
<date date-type="received">
<day>07</day>
<month>02</month>
<year>2024</year>
</date>
<date date-type="accepted">
<day>27</day>
<month>03</month>
<year>2024</year>
</date>
</history>
<permissions>
<copyright-statement>Copyright &#xa9; 2024 Peng, Yang, Luo, Yuan, Xiong, Ma and Yao</copyright-statement>
<copyright-year>2024</copyright-year>
<copyright-holder>Peng, Yang, Luo, Yuan, Xiong, Ma and Yao</copyright-holder>
<license xlink:href="http://creativecommons.org/licenses/by/4.0/">
<p>This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.</p>
</license>
</permissions>
<abstract>
<p>Hydroxychloroquine (HCQ) is used as a traditional disease-modifying antirheumatic drugs (DMARDs), for the treatment of autoimmune diseases such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). However, it can cause serious adverse reactions, including hyperpigmentation of the skin and bull&#x2019;s-eye macular lesions. Here, we present a case of HCQ-induced hyperpigmentation of the skin and bull&#x2019;s-eye macular lesions in a patient who received HCQ for RA. A 65-year-old female patient developed blurred vision and hyperpigmentation of multiple areas of skin over the body for one month after 3 years of HCQ treatment for RA. Based on clinical presentation, ophthalmological examination and dermatopathological biopsy, a diagnosis of drug-induced cutaneous hyperpigmentation and bullous maculopathy of the right eye was made. After discontinuation of HCQ and treatment with iguratimod tablets, the hyperpigmentation of the patient &#x2018;s skin was gradually reduced, and the symptoms of blurred vision were not significantly improved. We also reviewed the available literature on HCQ-induced cutaneous hyperpigmentation and bull&#x2019;s-eye macular lesions and described the clinical features of HCQ-induced cutaneous hyperpigmentation and bull&#x2019;s-eye macular lesions. In conclusion, clinicians should be aware of early cutaneous symptoms and HCQ-associated ophthalmotoxicity in patients with rheumatic diseases on HCQ sulphate and should actively monitor patients, have them undergo regular ophthalmological examinations and give appropriate treatment to prevent exacerbation of symptoms.</p>
</abstract>
<kwd-group>
<kwd>hydroxychloroquine</kwd>
<kwd>adverse drug reaction</kwd>
<kwd>hyperpigmentation of the skin</kwd>
<kwd>bull&#x2019;s-eye maculopathy</kwd>
<kwd>literature review</kwd>
<kwd>autoimmune disease</kwd>
</kwd-group>
<counts>
<fig-count count="5"/>
<table-count count="3"/>
<equation-count count="0"/>
<ref-count count="52"/>
<page-count count="9"/>
<word-count count="3078"/>
</counts>
<custom-meta-wrap>
<custom-meta>
<meta-name>section-in-acceptance</meta-name>
<meta-value>Autoimmune and Autoinflammatory Disorders : Autoimmune Disorders</meta-value>
</custom-meta>
</custom-meta-wrap>
</article-meta>
</front>
<body>
<sec id="s1" sec-type="intro">
<title>Introduction</title>
<p>Hydroxychloroquine (HCQ) is a 4-aminoquinoline antimalarial drug. It is commonly used as a sulfate, namely HCQ sulfate. Its antimalarial effect is the same as that of chloroquine, but its toxicity is only half that of chloroquine. In addition, HCQ sulfate also has anti-inflammatory, immunomodulatory and anticoagulant effects (<xref ref-type="bibr" rid="B1">1</xref>&#x2013;<xref ref-type="bibr" rid="B4">4</xref>), so it is widely used in clinical treatment of rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), Sj&#xf6;gren&#x2019;s syndrome, skin diseases, etc., and the adverse reactions are gradually increasing (<xref ref-type="bibr" rid="B5">5</xref>, <xref ref-type="bibr" rid="B6">6</xref>). There are fewer reports on HCQ-induced hyperpigmentation of the skin and macular lesions in the bull&#x2019;s eye. This article analyses the literature related to HCQ sulfate-induced hyperpigmentation of the skin and macular lesions in the bull&#x2019;s eye in conjunction with the literature review by taking a case of HCQ sulfate-induced hyperpigmentation and macular lesions in the bull&#x2019;s eye as an example in order to warn the clinic to fully understand the adverse effects of HCQ.</p>
</sec>
<sec id="s2">
<title>Case report</title>
<p>We assessed a 65-year-old female patient with RA in December 2023 who had been diagnosed with RA 10 years earlier and was now feeling pain in both shoulders, wrists, and finger joints of both hands with mild limitation of movement. The patient was treated with HCQ (400mg/d) and low-dose prednisolone (5 mg/d) for 3 years. The patient had no other comorbidities or medications, and for the past month felt blurred vision and noticed a darkening of the skin color. Our physical examination revealed excessive skin pigmentation in many parts of the body, especially in the head and face, neck, upper limbs and lower limbs (<xref ref-type="fig" rid="f1">
<bold>Figure&#xa0;1</bold>
</xref>). The patient attributed this to chronic ultraviolet light exposure.</p>
<fig id="f1" position="float">
<label>Figure&#xa0;1</label>
<caption>
<p>Hyperpigmentation of head, face, neck, upper limbs and lower limbs.</p>
</caption>
<graphic mimetype="image" mime-subtype="tiff" xlink:href="fimmu-15-1383343-g001.tif"/>
</fig>
<p>We performed relevant laboratory tests on the patient, which showed an elevated erythrocyte sedimentation rate of 61.00 mm/h (normal, 0-20 mm/L), an elevated rheumatoid factor of 43.15 IL/ml (normal, 0-20 IL/ml), and an elevated anti-cyclic citrullinated peptide antibody of &gt; 500.00 U/mL (normal, 0-20 U/mL). We performed an ophthalmological examination of the patient because he had symptoms of blurred vision and because studies have shown that HCQ can cause retinopathy (<xref ref-type="bibr" rid="B7">7</xref>, <xref ref-type="bibr" rid="B8">8</xref>). The visual field examination results showed that the visual field of the right eye showed a visual field defect outside the range of 45&#xb0; above and 25&#xb0; on the nasal side, and the light sensitivity of the remaining visual field decreased significantly. Compared with the dark spots around the physiological blind spots of the left eye, the photosensitivity decreased widely outside the range of 40&#xb0;, and the photosensitivity decreased scattered within the range of 40&#xb0;. Therefore, we performed optical coherence tomography (OCT) (<xref ref-type="fig" rid="f2">
<bold>Figure&#xa0;2</bold>
</xref>) and fundus screening (<xref ref-type="fig" rid="f3">
<bold>Figures&#xa0;3A-D</bold>
</xref>) on the patient. The results of OCT examination showed that the retinal pigment epithelium (RPE) layer in the macular area of the right eye was disordered and uneven, and irregular mass uplift was seen. The reflection of the ellipsoid zone and the IS/OS layer was interrupted and discontinuous. The RPE layer on the temporal side of the macular showed localized choroidal depression. The macular morphology was irregular, and the thickness of the macular fovea was significantly thinner (<xref ref-type="fig" rid="f2">
<bold>Figure&#xa0;2A</bold>
</xref>). However, the results of OCT of the left eye did not show any significant abnormality (<xref ref-type="fig" rid="f2">
<bold>Figure&#xa0;2B</bold>
</xref>). The results of fundus screening showed that the right eye had a round-like lesion in the macular area, about 2.5*3PD in size. The lesion was uneven yellow-white, and the center was dark brown. In conjunction with the OCT findings, a bull&#x2019;s eye macular lesion was considered.</p>
<fig id="f2" position="float">
<label>Figure&#xa0;2</label>
<caption>
<p>
<bold>(A)</bold> OCT results of the right eye; <bold>(B) </bold> OCT results of the left eye.</p>
</caption>
<graphic mimetype="image" mime-subtype="tiff" xlink:href="fimmu-15-1383343-g002.tif"/>
</fig>
<fig id="f3" position="float">
<label>Figure&#xa0;3</label>
<caption>
<p>
<bold>(A) </bold> Right anterior segment findings; <bold>(B)</bold> Right eye fundus screening results; <bold>(C)</bold> Left anterior segment findings; <bold>(D)</bold> Left eye fundus screening results.</p>
</caption>
<graphic mimetype="image" mime-subtype="tiff" xlink:href="fimmu-15-1383343-g003.tif"/>
</fig>
<p>From the results of the ophthalmologic examination, our patient was not considered for the diagnosis of age-related macular degeneration (AMD), which is characterized by the accumulation of extracellular deposits and the progressive degeneration of photoreceptors and adjacent tissues (<xref ref-type="bibr" rid="B9">9</xref>&#x2013;<xref ref-type="bibr" rid="B12">12</xref>). The prevalence increases gradually with age and usually affects vision for a short period of time, even leading to blindness (<xref ref-type="bibr" rid="B13">13</xref>, <xref ref-type="bibr" rid="B14">14</xref>). In AMD, the damage is concentrated in the central portion of the retina, known as the macula. One of the features of AMD is the scattered or confluent areas of degeneration of RPE cells and overlying photoreceptors in the photoreceptors of the photoreceptors, which depend on the RPE for trophic support. Although our patient&#x2019;s OCT results showed disturbed and uneven RPE reflection seen in the retina of the macular area of the right eye. However, there was no significant abnormality in the left eye OCT results. Another feature of AMD is the formation of choroidal neovascularization, in which immature blood vessels grow from the choroid below toward the outer retina. These immature blood vessels leak fluid below or inside the retina (<xref ref-type="bibr" rid="B10">10</xref>). In contrast, our patient&#x2019;s funduscopic findings showed no vasculopathy. So we consider that this macular lesion is not so much related to aging as it is to the use of HCQ.</p>
<p>In addition, we performed a skin biopsy on the patient. HE staining (<xref ref-type="fig" rid="f4">
<bold>Figure&#xa0;4A</bold>
</xref>) showed excessive keratinization of the epidermal mesh basket, a significant increase in melanin in the basal layer, sparse lymphocyte and tissue cell infiltration around the blood vessels in the superficial dermis, and a few melanocytes and melanin granules were seen locally, considering drug-induced pigmentation. Therefore, it can be differentiated from skin pigmentation caused by exposure to ultraviolet light (<xref ref-type="bibr" rid="B15">15</xref>). Fontana-Masson staining (<xref ref-type="fig" rid="f4">
<bold>Figure&#xa0;4B</bold>
</xref>) showed a significant increase in melanin in the basal layer of the epidermis and a few melanin granules in the superficial dermis. Prussian blue staining and silver hexamine staining were negative (<xref ref-type="fig" rid="f4">
<bold>Figures&#xa0;4C, D</bold>
</xref>). Five items of direct immunofluorescence (<xref ref-type="fig" rid="f5">
<bold>Figure&#xa0;5</bold>
</xref>) C3, IgG, IgM, IgA and Fib were all negative.</p>
<fig id="f4" position="float">
<label>Figure&#xa0;4</label>
<caption>
<p>
<bold>(A)</bold> HE staining; <bold>(B)</bold> Fontana-Masson staining; <bold>(C)</bold> Prussian blue staining; <bold>(D)</bold> silver hexamine staining.</p>
</caption>
<graphic mimetype="image" mime-subtype="tiff" xlink:href="fimmu-15-1383343-g004.tif"/>
</fig>
<fig id="f5" position="float">
<label>Figure&#xa0;5</label>
<caption>
<p>Direct immunofluorescence staining.</p>
</caption>
<graphic mimetype="image" mime-subtype="tiff" xlink:href="fimmu-15-1383343-g005.tif"/>
</fig>
<p>According to the patient &#x2018;s medical history and examination results, we believe that the patient &#x2018;s long-term use of HCQ in the treatment of RA, resulting in hyperpigmentation of the skin and bull&#x2019;s-eye maculopathy. Therefore, we decided to discontinue HCQ and replace it with iguratimod tablets (50mg/d) and prednisone acetate tablets (5mg/d) to control the disease. It is important to note that iguratimod is only used in China and Japan for the treatment of RA and has been shown to be effective (<xref ref-type="bibr" rid="B16">16</xref>&#x2013;<xref ref-type="bibr" rid="B18">18</xref>). Since then, we followed up the patient for three months. After discontinuation of HCQ and treatment with iguratimod tablets, the hyperpigmentation of the patient &#x2018;s skin was gradually reduced, and the symptoms of blurred vision were not significantly improved.</p>
</sec>
<sec id="s3" sec-type="discussion">
<title>Discussion</title>
<sec id="s3_1">
<title>Literature retrieval</title>
<p>Based on the patient&#x2019;s clinical presentation and ophthalmologic findings, we reviewed similar cases reported in PubMed, Embase, Web of Science and other databases from the establishment of the database to December 2023. We used &#x201c;hydroxychloroquine&#x201d;, &#x201c;plaquenil&#x201d;, &#x201c;case study&#x201d;, &#x201c;case report&#x201d;, &#x201c;bull&#x2019;s-eye maculopathy&#x201d; and &#x201c;hyperpigmentation&#x201d; as the search terms to filter out the eligible literature and extract the relevant information of the cases. From the results of our literature search, a total of 181 articles were retrieved from the literature related to hyperpigmentation of the skin. After screening, 18 articles were obtained, the total number of cases was 20, female patients were more than male patients, distributed in different countries or regions, the primary disease was mainly RA or SLE, the color of skin pigmentation was mainly blue/gray, and the site of skin pigmentation was mainly on the face, the upper limbs or the lower limbs, and the daily dosage of HCQ was mainly 400mg, and the skin pigmentation of the over-pigmented skin of the majority of the patients could be gradually subsided after stopping the HCQ. <xref ref-type="table" rid="T1">
<bold>Table&#xa0;1</bold>
</xref> shows the detailed clinical features of these cases. A total of 46 articles were retrieved from the literature related to macular degeneration of the bull&#x2019;s eye. After screening 11 valid literature were obtained, the total number of cases was 13, all were female patients, the daily dose of HCQ was 200-1200mg and the approximate cumulative dose was 438-2920g, and most of the patients&#x2019; solution was to stop HCQ therapy. <xref ref-type="table" rid="T2">
<bold>Table&#xa0;2</bold>
</xref> shows the detailed clinical features of these cases.</p>
<table-wrap id="T1" position="float">
<label>Table&#xa0;1</label>
<caption>
<p>Reported cases of hyperpigmentation of HCQ.</p>
</caption>
<table frame="hsides">
<thead>
<tr>
<th valign="middle" align="center">Year</th>
<th valign="middle" align="center">Country</th>
<th valign="middle" align="center">Study</th>
<th valign="middle" align="center">Sample size</th>
<th valign="middle" align="center">Age/Sex</th>
<th valign="middle" align="center">Primary disease</th>
<th valign="middle" align="center">Body parts of hyperpigmentation</th>
<th valign="middle" align="center">Dosage, mg/d</th>
<th valign="middle" align="center">Delay to onset of symptoms/months</th>
<th valign="middle" align="center">Symptoms after discontinuation of HCQ</th>
</tr>
</thead>
<tbody>
<tr>
<td valign="middle" align="center">2002</td>
<td valign="middle" align="center">USA</td>
<td valign="middle" align="left">Ture et&#xa0;al. (<xref ref-type="bibr" rid="B19">19</xref>)</td>
<td valign="middle" align="center">1</td>
<td valign="middle" align="center">Not reported</td>
<td valign="middle" align="center">RA</td>
<td valign="middle" align="left">(Black/gray) extremity, torso, hairline</td>
<td valign="middle" align="center">Not reported</td>
<td valign="middle" align="center">Not reported</td>
<td valign="middle" align="center">Not reported</td>
</tr>
<tr>
<td valign="middle" align="center">2004</td>
<td valign="middle" align="center">UK</td>
<td valign="middle" align="left">Millard et&#xa0;al. (<xref ref-type="bibr" rid="B20">20</xref>)</td>
<td valign="middle" align="center">1</td>
<td valign="middle" align="center">48/F</td>
<td valign="middle" align="center">Mixed connective tissue disease</td>
<td valign="middle" align="left">(Gray)face, neck, trunk, axillae, posterior thighs</td>
<td valign="middle" align="center">400</td>
<td valign="middle" align="center">12</td>
<td valign="middle" align="center">Not reported</td>
</tr>
<tr>
<td valign="middle" align="center">2006</td>
<td valign="middle" align="center">UK</td>
<td valign="middle" align="left">Reynaert et&#xa0;al. (<xref ref-type="bibr" rid="B21">21</xref>)</td>
<td valign="middle" align="center">2</td>
<td valign="middle" align="center">-/F</td>
<td valign="middle" align="center">SLE</td>
<td valign="middle" align="left">(Blue/gray) pretibial, face</td>
<td valign="middle" align="center">200-400</td>
<td valign="middle" align="center">18</td>
<td valign="middle" align="center">Not reported</td>
</tr>
<tr>
<td valign="middle" align="center">2007</td>
<td valign="middle" align="center">Israel</td>
<td valign="middle" align="left">Amichai et&#xa0;al. (<xref ref-type="bibr" rid="B22">22</xref>)</td>
<td valign="middle" align="center">1</td>
<td valign="middle" align="center">37/F</td>
<td valign="middle" align="center">RA</td>
<td valign="middle" align="left">(Blue/gray) thighs</td>
<td valign="middle" align="center">400</td>
<td valign="middle" align="center">12</td>
<td valign="middle" align="center">Pigmentation decreased</td>
</tr>
<tr>
<td valign="middle" align="center">2008</td>
<td valign="middle" align="center">Turkey</td>
<td valign="middle" align="left">Melikoglu et&#xa0;al. (<xref ref-type="bibr" rid="B23">23</xref>)</td>
<td valign="middle" align="center">1</td>
<td valign="middle" align="center">48/F</td>
<td valign="middle" align="center">SS</td>
<td valign="middle" align="left">(Blue/gray) dorsal hands</td>
<td valign="middle" align="center">400</td>
<td valign="middle" align="center">24</td>
<td valign="middle" align="center">Pigmentation decreased</td>
</tr>
<tr>
<td valign="middle" align="center">2008</td>
<td valign="middle" align="center">USA</td>
<td valign="middle" align="left">Puri et&#xa0;al. (<xref ref-type="bibr" rid="B24">24</xref>)</td>
<td valign="middle" align="center">2</td>
<td valign="middle" align="center">50/F 78/F</td>
<td valign="middle" align="center">Undifferentiated arthritis; SLE and RA</td>
<td valign="middle" align="left">(Gray)upper back, shoulders; (blue)temple</td>
<td valign="middle" align="center">400</td>
<td valign="middle" align="center">48-60/18</td>
<td valign="middle" align="center">Not reported</td>
</tr>
<tr>
<td valign="middle" align="center">2008</td>
<td valign="middle" align="center">Netherlands</td>
<td valign="middle" align="left">Rood et&#xa0;al. (<xref ref-type="bibr" rid="B25">25</xref>)</td>
<td valign="middle" align="center">1</td>
<td valign="middle" align="center">92/F</td>
<td valign="middle" align="center">RA</td>
<td valign="middle" align="left">(Gray)forearms</td>
<td valign="middle" align="center">400</td>
<td valign="middle" align="center">68</td>
<td valign="middle" align="center">Not reported</td>
</tr>
<tr>
<td valign="middle" align="center">2009</td>
<td valign="middle" align="center">USA</td>
<td valign="middle" align="left">Morrison et&#xa0;al. (<xref ref-type="bibr" rid="B26">26</xref>)</td>
<td valign="middle" align="center">1</td>
<td valign="middle" align="center">Not reported</td>
<td valign="middle" align="center">SLE</td>
<td valign="middle" align="left">(Blue/gray) shins, forearms, hands</td>
<td valign="middle" align="center">Not reported</td>
<td valign="middle" align="center">Not reported</td>
<td valign="middle" align="center">Not reported</td>
</tr>
<tr>
<td valign="middle" align="center">2012</td>
<td valign="middle" align="center">Korea</td>
<td valign="middle" align="left">Cho et&#xa0;al. (<xref ref-type="bibr" rid="B27">27</xref>)</td>
<td valign="middle" align="center">1</td>
<td valign="middle" align="center">58/F</td>
<td valign="middle" align="center">RA</td>
<td valign="middle" align="left">(Blue/gray) neck, upper trunk, upper extremities</td>
<td valign="middle" align="center">200</td>
<td valign="middle" align="center">48</td>
<td valign="middle" align="center">Not reported</td>
</tr>
<tr>
<td valign="middle" align="center">2013</td>
<td valign="middle" align="center">USA</td>
<td valign="middle" align="left">Mir et&#xa0;al. (<xref ref-type="bibr" rid="B28">28</xref>)</td>
<td valign="middle" align="center">1</td>
<td valign="middle" align="center">57/F</td>
<td valign="middle" align="center">SLE</td>
<td valign="middle" align="left">(Blue/gray) face, upper back, feet</td>
<td valign="middle" align="center">Not reported</td>
<td valign="middle" align="center">84</td>
<td valign="middle" align="center">Not reported</td>
</tr>
<tr>
<td valign="middle" align="center">2013</td>
<td valign="middle" align="center">USA</td>
<td valign="middle" align="left">Cohen et&#xa0;al. (<xref ref-type="bibr" rid="B29">29</xref>)</td>
<td valign="middle" align="center">1</td>
<td valign="middle" align="center">66/F</td>
<td valign="middle" align="center">SLE</td>
<td valign="middle" align="left">(Black)forehead, face, neck, v-area of the upper central chest; (blue)upper right chest</td>
<td valign="middle" align="center">400</td>
<td valign="middle" align="center">396</td>
<td valign="middle" align="center">Not reported</td>
</tr>
<tr>
<td valign="middle" align="center">2013</td>
<td valign="middle" align="center">Germany</td>
<td valign="middle" align="left">Tracy et&#xa0;al. (<xref ref-type="bibr" rid="B30">30</xref>)</td>
<td valign="middle" align="center">1</td>
<td valign="middle" align="center">48/F</td>
<td valign="middle" align="center">SLE</td>
<td valign="middle" align="left">(Gray)left forehead, nasal bridge, chest, upper back</td>
<td valign="middle" align="center">400</td>
<td valign="middle" align="center">216</td>
<td valign="middle" align="center">Pigmentation decreased</td>
</tr>
<tr>
<td valign="middle" align="center">2015</td>
<td valign="middle" align="center">USA</td>
<td valign="middle" align="left">Sawalha et&#xa0;al. (<xref ref-type="bibr" rid="B31">31</xref>)</td>
<td valign="middle" align="center">1</td>
<td valign="middle" align="center">32/F</td>
<td valign="middle" align="center">RA</td>
<td valign="middle" align="left">(Black/gray) neck, bilateral forearms, dorsal feet</td>
<td valign="middle" align="center">400</td>
<td valign="middle" align="center">3</td>
<td valign="middle" align="center">Pigmentation decreased</td>
</tr>
<tr>
<td valign="middle" align="center">2017</td>
<td valign="middle" align="center">France</td>
<td valign="middle" align="left">Coulombe et&#xa0;al. (<xref ref-type="bibr" rid="B32">32</xref>)</td>
<td valign="middle" align="center">1</td>
<td valign="middle" align="center">48/M</td>
<td valign="middle" align="center">SLE</td>
<td valign="middle" align="left">(Blue/gray) face, arms, legs</td>
<td valign="middle" align="center">Not reported</td>
<td valign="middle" align="center">240</td>
<td valign="middle" align="center">Not reported</td>
</tr>
<tr>
<td valign="middle" align="center">2018</td>
<td valign="middle" align="center">Portugal</td>
<td valign="middle" align="left">Ivo et&#xa0;al. (<xref ref-type="bibr" rid="B33">33</xref>)</td>
<td valign="middle" align="center">1</td>
<td valign="middle" align="center">80/F</td>
<td valign="middle" align="center">SLE and SS</td>
<td valign="middle" align="left">(Brown to grey/black) face, anterior side of legs, forearms</td>
<td valign="middle" align="center">400</td>
<td valign="middle" align="center">132</td>
<td valign="middle" align="center">Not reported</td>
</tr>
<tr>
<td valign="middle" align="center">2018</td>
<td valign="middle" align="center">India</td>
<td valign="middle" align="left">Thakur et&#xa0;al. (<xref ref-type="bibr" rid="B34">34</xref>)</td>
<td valign="middle" align="center">1</td>
<td valign="middle" align="center">-/F</td>
<td valign="middle" align="center">Granuloma annulare</td>
<td valign="middle" align="left">(Blue/gray) extremities, upper back, neck</td>
<td valign="middle" align="center">300</td>
<td valign="middle" align="center">4</td>
<td valign="middle" align="center">Not reported</td>
</tr>
<tr>
<td valign="middle" align="center">2018</td>
<td valign="middle" align="center">Greece</td>
<td valign="middle" align="left">Tosios et&#xa0;al. (<xref ref-type="bibr" rid="B35">35</xref>)</td>
<td valign="middle" align="center">1</td>
<td valign="middle" align="center">53/F</td>
<td valign="middle" align="center">RA</td>
<td valign="middle" align="left">(Blue/gray) neck, thorax</td>
<td valign="middle" align="center">400</td>
<td valign="middle" align="center">60</td>
<td valign="middle" align="center">Pigmentation decreased</td>
</tr>
<tr>
<td valign="middle" align="center">2018</td>
<td valign="middle" align="center">Turkey</td>
<td valign="middle" align="left">Tekg&#xf6;z et&#xa0;al. (<xref ref-type="bibr" rid="B36">36</xref>)</td>
<td valign="middle" align="center">1</td>
<td valign="middle" align="center">60/M</td>
<td valign="middle" align="center">RA</td>
<td valign="middle" align="left">(Brown/black) face, neck</td>
<td valign="middle" align="center">400</td>
<td valign="middle" align="center">12</td>
<td valign="middle" align="center">Pigmentation decreased</td>
</tr>
</tbody>
</table>
<table-wrap-foot>
<fn>
<p>F, female; M, male; RA, rheumatoid arthritis; SLE, systemic lupus erythematosus; SS, Sj&#xf6;gren&#x2019;s syndrome.</p>
</fn>
</table-wrap-foot>
</table-wrap>
<table-wrap id="T2" position="float">
<label>Table&#xa0;2</label>
<caption>
<p>Reported Adverse Ocular Region Effects of HCQ.</p>
</caption>
<table frame="hsides">
<thead>
<tr>
<th valign="middle" align="center">Year</th>
<th valign="middle" align="center">Study</th>
<th valign="middle" align="center">Number of cases</th>
<th valign="middle" align="center">Age/Sex</th>
<th valign="middle" align="center">Dosage(mg/d)</th>
<th valign="middle" align="center">Approximate cumulative dose (g)</th>
<th valign="middle" align="center">The duration of HCQ use(years)</th>
<th valign="middle" align="center">Types of adverse reactions</th>
<th valign="middle" align="center">Resolution</th>
</tr>
</thead>
<tbody>
<tr>
<td valign="middle" align="center">1967</td>
<td valign="middle" align="left">Shearer et&#xa0;al. (<xref ref-type="bibr" rid="B37">37</xref>)</td>
<td valign="middle" align="center">1</td>
<td valign="middle" align="center">37/F</td>
<td valign="middle" align="center">600-1200</td>
<td valign="middle" align="center">770</td>
<td valign="middle" align="center">2.21</td>
<td valign="middle" align="left">Visual loss and bilateral bull&#x2019;s-eye macular degeneration</td>
<td valign="middle" align="left">cessation of HCQ</td>
</tr>
<tr>
<td valign="middle" align="center">1987</td>
<td valign="middle" align="left">Johnson et&#xa0;al. (<xref ref-type="bibr" rid="B38">38</xref>)</td>
<td valign="middle" align="center">1</td>
<td valign="middle" align="center">43/F</td>
<td valign="middle" align="center">500</td>
<td valign="middle" align="center">730</td>
<td valign="middle" align="center">4</td>
<td valign="middle" align="left">Bilateral pericentral scotomata with a bull&#x2019;s-eye maculopathy</td>
<td valign="middle" align="left">cessation of HCQ</td>
</tr>
<tr>
<td valign="middle" align="center">1991</td>
<td valign="middle" align="left">Weiner et&#xa0;al. (<xref ref-type="bibr" rid="B39">39</xref>)</td>
<td valign="middle" align="center">2</td>
<td valign="middle" align="center">49/F, 60/F</td>
<td valign="middle" align="center">400-800, 400</td>
<td valign="middle" align="center">1788, 2920</td>
<td valign="middle" align="center">10, 20</td>
<td valign="middle" align="left">Bull&#x2019;s-eye maculopathy, window defect was evident by fluorescein angiography in both eyes</td>
<td valign="middle" align="left">cessation of HCQ</td>
</tr>
<tr>
<td valign="middle" align="center">2007</td>
<td valign="middle" align="left">Fung et&#xa0;al. (<xref ref-type="bibr" rid="B40">40</xref>)</td>
<td valign="middle" align="center">1</td>
<td valign="middle" align="center">48/F</td>
<td valign="middle" align="center">400</td>
<td valign="middle" align="center">1168</td>
<td valign="middle" align="center">8</td>
<td valign="middle" align="left">Bull&#x2019;s-eye maculopathy</td>
<td valign="middle" align="left">Not reported</td>
</tr>
<tr>
<td valign="middle" align="center">2010</td>
<td valign="middle" align="left">Salu et&#xa0;al. (<xref ref-type="bibr" rid="B41">41</xref>)</td>
<td valign="middle" align="center">1</td>
<td valign="middle" align="center">43/F</td>
<td valign="middle" align="center">600</td>
<td valign="middle" align="center">657</td>
<td valign="middle" align="center">3</td>
<td valign="middle" align="left">Early stage of bull&#x2019;s-eye maculopathy</td>
<td valign="middle" align="left">cessation of HCQ</td>
</tr>
<tr>
<td valign="middle" align="center">2014</td>
<td valign="middle" align="left">Phillips et&#xa0;al. (<xref ref-type="bibr" rid="B42">42</xref>)</td>
<td valign="middle" align="center">1</td>
<td valign="middle" align="center">56/F</td>
<td valign="middle" align="center">400</td>
<td valign="middle" align="center">584</td>
<td valign="middle" align="center">4</td>
<td valign="middle" align="left">Bilateral bull&#x2019;s-eye macular lesions</td>
<td valign="middle" align="left">Not reported</td>
</tr>
<tr>
<td valign="middle" align="center">2015</td>
<td valign="middle" align="left">Wong et&#xa0;al. (<xref ref-type="bibr" rid="B43">43</xref>)</td>
<td valign="middle" align="center">2</td>
<td valign="middle" align="center">68/F</td>
<td valign="middle" align="center">Not reported</td>
<td valign="middle" align="center">1168</td>
<td valign="middle" align="center">8</td>
<td valign="middle" align="left">Bull&#x2019;s-eye maculopathy</td>
<td valign="middle" align="left">Not reported</td>
</tr>
<tr>
<td valign="middle" align="center">2016</td>
<td valign="middle" align="left">Brandao et&#xa0;al. (<xref ref-type="bibr" rid="B44">44</xref>)</td>
<td valign="middle" align="center">1</td>
<td valign="middle" align="center">15/F</td>
<td valign="middle" align="center">200</td>
<td valign="middle" align="center">438</td>
<td valign="middle" align="center">3</td>
<td valign="middle" align="left">Bull&#x2019;s-eye maculopathy</td>
<td valign="middle" align="left">cessation of HCQ</td>
</tr>
<tr>
<td valign="middle" align="center">2019</td>
<td valign="middle" align="left">Modi et&#xa0;al. (<xref ref-type="bibr" rid="B45">45</xref>)</td>
<td valign="middle" align="center">1</td>
<td valign="middle" align="center">60/F</td>
<td valign="middle" align="center">400</td>
<td valign="middle" align="center">2044</td>
<td valign="middle" align="center">14</td>
<td valign="middle" align="left">Bull&#x2019;s-eye maculopathy</td>
<td valign="middle" align="left">cessation of HCQ</td>
</tr>
<tr>
<td valign="middle" align="center">2020</td>
<td valign="middle" align="left">Pellerano et&#xa0;al. (<xref ref-type="bibr" rid="B46">46</xref>)</td>
<td valign="middle" align="center">1</td>
<td valign="middle" align="center">28/F</td>
<td valign="middle" align="center">Not reported</td>
<td valign="middle" align="center">1369</td>
<td valign="middle" align="center">15</td>
<td valign="middle" align="left">Bull&#x2019;s-eye maculopathy</td>
<td valign="middle" align="left">cessation of HCQ</td>
</tr>
<tr>
<td valign="middle" align="center">2022</td>
<td valign="middle" align="left">Ameen Ismail et&#xa0;al. (<xref ref-type="bibr" rid="B47">47</xref>)</td>
<td valign="middle" align="center">1</td>
<td valign="middle" align="center">42/F</td>
<td valign="middle" align="center">Not reported</td>
<td valign="middle" align="center">Not reported</td>
<td valign="middle" align="center">1.33</td>
<td valign="middle" align="left">Macular degeneration of the left bull&#x2019;s eye</td>
<td valign="middle" align="left">Not reported</td>
</tr>
</tbody>
</table>
<table-wrap-foot>
<fn>
<p>F, female; HCQ, hydroxychloroquine.</p>
</fn>
</table-wrap-foot>
</table-wrap>
</sec>
<sec id="s3_2">
<title>Hyperpigmentation of skin induced by HCQ</title>
<p>Hyperpigmentation of the skin caused by antimalarial treatment has been reported since the Second World War (<xref ref-type="bibr" rid="B48">48</xref>). However, the associated skin hyperpigmentation due to HCQ seems to be uncommon compared to other antimalarials such as chloroquine (<xref ref-type="bibr" rid="B28">28</xref>, <xref ref-type="bibr" rid="B49">49</xref>). One study showed that the onset of HCQ-associated skin hyperpigmentation ranged from 3 months to 22 years after the start of treatment, with a median of 6.1 years (<xref ref-type="bibr" rid="B50">50</xref>). In our reported case, the patient developed hyperpigmentation of the skin about 3 years after the start of treatment, and the treatment was to discontinue HCQs and to control the RA with iguratimod tablets, which led to a gradual reduction of the patient&#x2019;s skin hyperpigmentation over several months (<xref ref-type="bibr" rid="B22">22</xref>, <xref ref-type="bibr" rid="B25">25</xref>). Although there is evidence that both melanin and iron deposition can be present in the dermis in HCQ-induced hyperpigmented skin lesions (<xref ref-type="bibr" rid="B50">50</xref>), the exact mechanism is unknown (<xref ref-type="bibr" rid="B30">30</xref>). Our patients completed the relevant pathological examination. Fontana-Masson staining (<xref ref-type="fig" rid="f4">
<bold>Figure&#xa0;4B</bold>
</xref>) showed a significant increase in melanin in the basal layer of the epidermis and a few melanin granules in the superficial layer of the dermis. Prussian blue staining was negative (<xref ref-type="fig" rid="f4">
<bold>Figure&#xa0;4C</bold>
</xref>). Therefore, we describe the pathological features of some cases (<xref ref-type="table" rid="T3">
<bold>Table&#xa0;3</bold>
</xref>). In terms of treatment, most of the investigators took the approach of discontinuing HCQ treatment to prevent further exacerbation of HCQ-induced hyperpigmentation of the skin. Most patients were able to reduce their hyperpigmentation after discontinuing HCQ treatment.</p>
<table-wrap id="T3" position="float">
<label>Table&#xa0;3</label>
<caption>
<p>Pathological features of some cases.</p>
</caption>
<table frame="hsides">
<thead>
<tr>
<th valign="middle" align="center">Year</th>
<th valign="middle" align="center">Study</th>
<th valign="middle" align="center">Skin biopsy</th>
<th valign="middle" align="center">Staining</th>
</tr>
</thead>
<tbody>
<tr>
<td valign="middle" align="center">2006</td>
<td valign="middle" align="left">Reynaert et&#xa0;al. (<xref ref-type="bibr" rid="B21">21</xref>)</td>
<td valign="middle" align="left">Granular pigment deposition</td>
<td valign="middle" align="left">Not reported</td>
</tr>
<tr>
<td valign="middle" align="center">2007</td>
<td valign="middle" align="left">Amichai et&#xa0;al. (<xref ref-type="bibr" rid="B22">22</xref>)</td>
<td valign="middle" align="left">Basal hyperpigmentation</td>
<td valign="middle" align="left">Not reported</td>
</tr>
<tr>
<td valign="middle" align="center">2008</td>
<td valign="middle" align="left">Puri et&#xa0;al. (<xref ref-type="bibr" rid="B24">24</xref>)</td>
<td valign="middle" align="left">Granular pigment deposition</td>
<td valign="middle" align="left">Perls Prussian staining was negative; Fontana-Masson staining was positive</td>
</tr>
<tr>
<td valign="middle" align="center">2008</td>
<td valign="middle" align="left">Rood et&#xa0;al. (<xref ref-type="bibr" rid="B25">25</xref>)</td>
<td valign="middle" align="left">Basal epidermal hyperpigmentation</td>
<td valign="middle" align="left">Schmorl staining was positive; Iron staining was positive</td>
</tr>
<tr>
<td valign="middle" align="center">2012</td>
<td valign="middle" align="left">Cho et&#xa0;al. (<xref ref-type="bibr" rid="B27">27</xref>)</td>
<td valign="middle" align="left">Epidermal melanin pigment and superficial dermal, yellow to brown colored granular pigment depositions</td>
<td valign="middle" align="left">Not reported</td>
</tr>
<tr>
<td valign="middle" align="center">2013</td>
<td valign="middle" align="left">Mir et&#xa0;al. (<xref ref-type="bibr" rid="B28">28</xref>)</td>
<td valign="middle" align="left">Yellow brown, non-refractile and coarsely granular pigment deposits</td>
<td valign="middle" align="left">Fontana-Masson staining was positive</td>
</tr>
<tr>
<td valign="middle" align="center">2013</td>
<td valign="middle" align="left">Cohen et&#xa0;al. (<xref ref-type="bibr" rid="B29">29</xref>)</td>
<td valign="middle" align="left">Yellow-to-brown granules scattered throughout the reticular dermis</td>
<td valign="middle" align="left">Perls Prussian staining was positive; Fontana-Masson staining was positive</td>
</tr>
<tr>
<td valign="middle" align="center">2013</td>
<td valign="middle" align="left">Tracy et&#xa0;al. (<xref ref-type="bibr" rid="B30">30</xref>)</td>
<td valign="middle" align="left">Demonstrated pigment within macrophages and within dermal dendrocytes</td>
<td valign="middle" align="left">Perls Prussian staining was positive; Fontana-Masson staining was positive</td>
</tr>
<tr>
<td valign="middle" align="center">2017</td>
<td valign="middle" align="left">Coulombe et&#xa0;al. (<xref ref-type="bibr" rid="B32">32</xref>)</td>
<td valign="middle" align="left">Yellow brown, nonrefractile and coarsely granular pigment deposition</td>
<td valign="middle" align="left">Perls Prussian staining was positive; Fontana-Masson staining was positive</td>
</tr>
<tr>
<td valign="middle" align="center">2018</td>
<td valign="middle" align="left">Ivo et&#xa0;al. (<xref ref-type="bibr" rid="B33">33</xref>)</td>
<td valign="middle" align="left">Pigment deposition in superficial dermis</td>
<td valign="middle" align="left">Perls Prussian staining was positive; Fontana-Masson staining was negative</td>
</tr>
<tr>
<td valign="middle" align="center">2018</td>
<td valign="middle" align="left">Thakur et&#xa0;al. (<xref ref-type="bibr" rid="B34">34</xref>)</td>
<td valign="middle" align="left">Brown coarse pigment in the dermis</td>
<td valign="middle" align="left">Perls Prussian staining was negative</td>
</tr>
<tr>
<td valign="middle" align="center">2018</td>
<td valign="middle" align="left">Tekg&#xf6;z et&#xa0;al. (<xref ref-type="bibr" rid="B36">36</xref>)</td>
<td valign="middle" align="left">Accumulation of pigment granules within the collagen fibers and macrophages along with the granules present freely in the tissue</td>
<td valign="middle" align="left">Not reported</td>
</tr>
</tbody>
</table>
</table-wrap>
</sec>
<sec id="s3_3">
<title>Retinal toxicity due to HCQ</title>
<p>Long-term treatment with HCQ can lead to retinal toxicity (<xref ref-type="bibr" rid="B51">51</xref>). This retinal change is typically characterized by a thinning of the photoreceptor layer, starting with a paracentral sulcus ring and progressing over time to a &#x201c;bull&#x2019;s-eye&#x201d; maculopathy, caused by pericentral atrophy and retention of the central sulcus (<xref ref-type="bibr" rid="B52">52</xref>). Some researchers have suggested that HCQ may be associated with bilateral retinopathy involving not only the macula but also the peripheral retina (<xref ref-type="bibr" rid="B39">39</xref>). The relationship between HCQ-related skin pigmentation and ocular toxicity is currently unknown (<xref ref-type="bibr" rid="B28">28</xref>); However, there is a need for regular ophthalmological follow-ups so that the patient&#x2019;s eye condition can be understood (<xref ref-type="bibr" rid="B30">30</xref>). Our patient developed vision loss after 36 months of HCQ treatment, with a cumulative dose of about 438 g. Ophthalmological examination revealed macular lesions in the right eye. <xref ref-type="table" rid="T2">
<bold>Table&#xa0;2</bold>
</xref> describes some of the published information on similar cases, and the case we reported is similar to those reported in the literature. In terms of treatment, most of the investigators took to discontinuing HCQ treatment to prevent further worsening of the ocular adverse effects caused by HCQ. However, patients who have developed bull&#x2019;s-eye macular degeneration are difficult to rehabilitate (<xref ref-type="bibr" rid="B41">41</xref>). In terms of ophthalmic examination, Fung et&#xa0;al. (<xref ref-type="bibr" rid="B40">40</xref>) suggest that OCT may be a useful, non-invasive clinical assessment if a patient presents with new visual changes associated with HCQ. In addition, OCT findings of diffuse retinal atrophy or increased reflectivity around the macular central pucker can support the port suspected diagnosis of HCQ-associated retinal toxicity.</p>
</sec>
</sec>
<sec id="s4" sec-type="conclusion">
<title>Conclusion</title>
<p>In conclusion, HCQ can cause adverse reactions such as hyperpigmentation of the skin and macular degeneration of the bull&#x2019;s eye, clinicians should be aware of early cutaneous symptoms and HCQ-associated ophthalmotoxicity in patients with rheumatic diseases on HCQ sulphate and should actively monitor patients, have them undergo regular ophthalmological examinations and give appropriate treatment to prevent exacerbation of symptoms.</p>
</sec>
<sec id="s5" sec-type="data-availability">
<title>Data availability statement</title>
<p>The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding author.</p>
</sec>
<sec id="s6" sec-type="ethics-statement">
<title>Ethics statement</title>
<p>The studies involving humans were approved by Ethics Committee of the Second Affiliated Hospital of Guizhou University of Traditional Chinese Medicine. The studies were conducted in accordance with the local legislation and institutional requirements. The participants provided their written informed consent to participate in this study. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.</p>
</sec>
<sec id="s7" sec-type="author-contributions">
<title>Author contributions</title>
<p>J-PP: Writing &#x2013; original draft, Writing &#x2013; review &amp; editing. X-YY: Writing &#x2013; original draft. FL: Writing &#x2013; original draft. X-MY: Writing &#x2013; original draft. HX: Writing &#x2013; original draft. W-KM: Writing &#x2013; original draft. X-MY: Writing &#x2013; original draft, Writing &#x2013; review &amp; editing.</p>
</sec>
</body>
<back>
<sec id="s8" sec-type="funding-information">
<title>Funding</title>
<p>The author(s) declare financial support was received for the research, authorship, and/or publication of this article. The study was funded by the National Natural Science Foundation of China, 82160869, 82374494; Guizhou Provincial Key Technology R&amp;D Program, Qiankehe Support [2021] General 006; Guizhou Provincial Basic Research Program(Natural Science) Qiankehe Basic-ZK[2023] General 412; Guizhou Kehe Academic New Seedling[2023-36]; Guizhou University of Traditional Chinese Medicine National and Provincial Scientific and Technological Innovation Talent Teams Cultivation Project, Guizhou University of Traditional Chinese Medicine TD He Zi [2022]004.</p>
</sec>
<ack>
<title>Acknowledgments</title>
<p>We appreciate Yuzheng Yang (Organization: Guizhou University of Traditional Chinese Medicine, Guiyang, China) for organizing the data, Yuheng Shi and Shasha Du (Organization: Ophthalmology Department, Second Affiliated Hospital of Guizhou University of Traditional Chinese Medicine, Guiyang, China) for performing the ophthalmologic examinations, and all authors for their cooperation.</p>
</ack>
<sec id="s9" sec-type="COI-statement">
<title>Conflict of interest</title>
<p>The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.</p>
</sec>
<sec id="s10" sec-type="disclaimer">
<title>Publisher&#x2019;s note</title>
<p>All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.</p>
</sec>
<ref-list>
<title>References</title>
<ref id="B1">
<label>1</label>
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Al-Bari</surname> <given-names>MA</given-names>
</name>
</person-group>. <article-title>Chloroquine analogues in drug discovery: new directions of uses, mechanisms of actions and toxic manifestations from malaria to multifarious diseases</article-title>. <source>J Antimicrob Chemother</source>. (<year>2015</year>) <volume>70</volume>:<page-range>1608&#x2013;21</page-range>. doi:&#xa0;<pub-id pub-id-type="doi">10.1093/jac/dkv018</pub-id>
</citation>
</ref>
<ref id="B2">
<label>2</label>
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Bai</surname> <given-names>L</given-names>
</name>
<name>
<surname>Li</surname> <given-names>H</given-names>
</name>
<name>
<surname>Li</surname> <given-names>J</given-names>
</name>
<name>
<surname>Song</surname> <given-names>J</given-names>
</name>
<name>
<surname>Zhou</surname> <given-names>Y</given-names>
</name>
<name>
<surname>Liu</surname> <given-names>B</given-names>
</name>
<etal/>
</person-group>. <article-title>Immunosuppressive effect of artemisinin and hydroxychloroquine combination therapy on IgA nephropathy via regulating the differentiation of CD4+ T cell subsets in rats</article-title>. <source>Int Immunopharmacol</source>. (<year>2019</year>) <volume>70</volume>:<page-range>313&#x2013;23</page-range>. doi:&#xa0;<pub-id pub-id-type="doi">10.1016/j.intimp.2019.02.056</pub-id>
</citation>
</ref>
<ref id="B3">
<label>3</label>
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Chandler</surname> <given-names>LC</given-names>
</name>
<name>
<surname>Yusuf</surname> <given-names>IH</given-names>
</name>
<name>
<surname>McClements</surname> <given-names>ME</given-names>
</name>
<name>
<surname>Barnard</surname> <given-names>AR</given-names>
</name>
<name>
<surname>MacLaren</surname> <given-names>RE</given-names>
</name>
<name>
<surname>Xue</surname> <given-names>K</given-names>
</name>
</person-group>. <article-title>Immunomodulatory effects of hydroxychloroquine and chloroquine in viral infections and their potential application in retinal gene therapy</article-title>. <source>Int J Mol Sci</source>. (<year>2020</year>) <volume>21</volume>:<page-range>1</page-range>. doi:&#xa0;<pub-id pub-id-type="doi">10.3390/ijms21144972</pub-id>
</citation>
</ref>
<ref id="B4">
<label>4</label>
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Richard</surname> <given-names>SA</given-names>
</name>
<name>
<surname>Kampo</surname> <given-names>S</given-names>
</name>
<name>
<surname>Hechavarria</surname> <given-names>ME</given-names>
</name>
<name>
<surname>Sackey</surname> <given-names>M</given-names>
</name>
<name>
<surname>Buunaaim</surname> <given-names>ADB</given-names>
</name>
<name>
<surname>Kuugbee</surname> <given-names>ED</given-names>
</name>
<etal/>
</person-group>. <article-title>Elucidating the pivotal immunomodulatory and anti-inflammatory potentials of chloroquine and hydroxychloroquine</article-title>. <source>J Immunol Res</source>. (<year>2020</year>) <volume>2020</volume>:<elocation-id>4582612</elocation-id>. doi:&#xa0;<pub-id pub-id-type="doi">10.1155/2020/4582612</pub-id>
</citation>
</ref>
<ref id="B5">
<label>5</label>
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Nirk</surname> <given-names>EL</given-names>
</name>
<name>
<surname>Reggiori</surname> <given-names>F</given-names>
</name>
<name>
<surname>Mauthe</surname> <given-names>M</given-names>
</name>
</person-group>. <article-title>Hydroxychloroquine in rheumatic autoimmune disorders and beyond</article-title>. <source>EMBO Mol Med</source>. (<year>2020</year>) <volume>12</volume>:<elocation-id>e12476</elocation-id>. doi:&#xa0;<pub-id pub-id-type="doi">10.15252/emmm.202012476</pub-id>
</citation>
</ref>
<ref id="B6">
<label>6</label>
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Schrezenmeier</surname> <given-names>E</given-names>
</name>
<name>
<surname>D&#xf6;rner</surname> <given-names>T</given-names>
</name>
</person-group>. <article-title>Mechanisms of action of hydroxychloroquine and chloroquine: implications for rheumatology</article-title>. <source>Nat Rev Rheumatol</source>. (<year>2020</year>) <volume>16</volume>:<page-range>155&#x2013;66</page-range>. doi:&#xa0;<pub-id pub-id-type="doi">10.1038/s41584-020-0372-x</pub-id>
</citation>
</ref>
<ref id="B7">
<label>7</label>
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Alveyn</surname> <given-names>E</given-names>
</name>
<name>
<surname>Galloway</surname> <given-names>J</given-names>
</name>
</person-group>. <article-title>When should we start screening for hydroxychloroquine retinopathy</article-title>? <source>Rheumatol (Oxford England)</source>. (<year>2022</year>) <volume>61</volume>:<page-range>3097&#x2013;8</page-range>. doi:&#xa0;<pub-id pub-id-type="doi">10.1093/rheumatology/keac043</pub-id>
</citation>
</ref>
<ref id="B8">
<label>8</label>
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Proano</surname> <given-names>C</given-names>
</name>
<name>
<surname>Kimball</surname> <given-names>GP</given-names>
</name>
</person-group>. <article-title>Hydroxychloroquine retinal toxicity</article-title>. <source>New Engl J Med</source>. (<year>2019</year>) <volume>380</volume>:<elocation-id>e27</elocation-id>. doi:&#xa0;<pub-id pub-id-type="doi">10.1056/NEJMicm1304542</pub-id>
</citation>
</ref>
<ref id="B9">
<label>9</label>
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Fleckenstein</surname> <given-names>M</given-names>
</name>
<name>
<surname>Keenan</surname> <given-names>TDL</given-names>
</name>
<name>
<surname>Guymer</surname> <given-names>RH</given-names>
</name>
<name>
<surname>Chakravarthy</surname> <given-names>U</given-names>
</name>
<name>
<surname>Schmitz-Valckenberg</surname> <given-names>S</given-names>
</name>
<name>
<surname>Klaver</surname> <given-names>CC</given-names>
</name>
<etal/>
</person-group>. <article-title>Age-related macular degeneration</article-title>. <source>Nat Rev Dis Primers</source>. (<year>2021</year>) <volume>7</volume>:<fpage>31</fpage>. doi:&#xa0;<pub-id pub-id-type="doi">10.1038/s41572-021-00265-2</pub-id>
</citation>
</ref>
<ref id="B10">
<label>10</label>
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Ambati</surname> <given-names>J</given-names>
</name>
<name>
<surname>Fowler</surname> <given-names>BJ</given-names>
</name>
</person-group>. <article-title>Mechanisms of age-related macular degeneration</article-title>. <source>Neuron</source>. (<year>2012</year>) <volume>75</volume>:<fpage>26</fpage>&#x2013;<lpage>39</lpage>. doi:&#xa0;<pub-id pub-id-type="doi">10.1016/j.neuron.2012.06.018</pub-id>
</citation>
</ref>
<ref id="B11">
<label>11</label>
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Chirco</surname> <given-names>KR</given-names>
</name>
<name>
<surname>Potempa</surname> <given-names>LA</given-names>
</name>
</person-group>. <article-title>C-reactive protein as a mediator of complement activation and inflammatory signaling in age-related macular degeneration</article-title>. <source>Front Immunol</source>. (<year>2018</year>) <volume>9</volume>:<elocation-id>539</elocation-id>. doi:&#xa0;<pub-id pub-id-type="doi">10.3389/fimmu.2018.00539</pub-id>
</citation>
</ref>
<ref id="B12">
<label>12</label>
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Clark</surname> <given-names>SJ</given-names>
</name>
<name>
<surname>McHarg</surname> <given-names>S</given-names>
</name>
<name>
<surname>Tilakaratna</surname> <given-names>V</given-names>
</name>
<name>
<surname>Brace</surname> <given-names>N</given-names>
</name>
<name>
<surname>Bishop</surname> <given-names>PN</given-names>
</name>
</person-group>. <article-title>Bruch's membrane compartmentalizes complement regulation in the eye with implications for therapeutic design in age-related macular degeneration</article-title>. <source>Front Immunol</source>. (<year>2017</year>) <volume>8</volume>:<elocation-id>1778</elocation-id>. doi:&#xa0;<pub-id pub-id-type="doi">10.3389/fimmu.2017.01778</pub-id>
</citation>
</ref>
<ref id="B13">
<label>13</label>
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Friedman</surname> <given-names>DS</given-names>
</name>
<name>
<surname>O'Colmain</surname> <given-names>BJ</given-names>
</name>
<name>
<surname>Mu&#xf1;oz</surname> <given-names>B</given-names>
</name>
<name>
<surname>Tomany</surname> <given-names>SC</given-names>
</name>
<name>
<surname>McCarty</surname> <given-names>C</given-names>
</name>
<name>
<surname>de Jong</surname> <given-names>PT</given-names>
</name>
<etal/>
</person-group>. <article-title>Prevalence of age-related macular degeneration in the United States</article-title>. <source>Arch Ophthalmol (Chicago Ill 1960)</source>. (<year>2004</year>) <volume>122</volume>:<page-range>564&#x2013;72</page-range>. doi:&#xa0;<pub-id pub-id-type="doi">10.1001/archopht.122.4.564</pub-id>
</citation>
</ref>
<ref id="B14">
<label>14</label>
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Wong</surname> <given-names>TY</given-names>
</name>
<name>
<surname>Chakravarthy</surname> <given-names>U</given-names>
</name>
<name>
<surname>Klein</surname> <given-names>R</given-names>
</name>
<name>
<surname>Mitchell</surname> <given-names>P</given-names>
</name>
<name>
<surname>Zlateva</surname> <given-names>G</given-names>
</name>
<name>
<surname>Buggage</surname> <given-names>R</given-names>
</name>
<etal/>
</person-group>. <article-title>The natural history and prognosis of neovascular age-related macular degeneration: a systematic review of the literature and meta-analysis</article-title>. <source>Ophthalmology</source>. (<year>2008</year>) <volume>115</volume>:<page-range>116&#x2013;26</page-range>. doi:&#xa0;<pub-id pub-id-type="doi">10.1016/j.ophtha.2007.03.008</pub-id>
</citation>
</ref>
<ref id="B15">
<label>15</label>
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>D'Orazio</surname> <given-names>J</given-names>
</name>
<name>
<surname>Jarrett</surname> <given-names>S</given-names>
</name>
<name>
<surname>Amaro-Ortiz</surname> <given-names>A</given-names>
</name>
<name>
<surname>Scott</surname> <given-names>T</given-names>
</name>
</person-group>. <article-title>UV radiation and the skin</article-title>. <source>Int J Mol Sci</source>. (<year>2013</year>) <volume>14</volume>:<page-range>12222&#x2013;48</page-range>. doi:&#xa0;<pub-id pub-id-type="doi">10.3390/ijms140612222</pub-id>
</citation>
</ref>
<ref id="B16">
<label>16</label>
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Hu</surname> <given-names>CJ</given-names>
</name>
<name>
<surname>Zhang</surname> <given-names>L</given-names>
</name>
<name>
<surname>Zhou</surname> <given-names>S</given-names>
</name>
<name>
<surname>Jiang</surname> <given-names>N</given-names>
</name>
<name>
<surname>Zhao</surname> <given-names>JL</given-names>
</name>
<name>
<surname>Wang</surname> <given-names>Q</given-names>
</name>
<etal/>
</person-group>. <article-title>Effectiveness of iguratimod as monotherapy or combined therapy in patients with rheumatoid arthritis: a systematic review and meta-analysis of RCTs</article-title>. <source>J orthopaedic Surg Res</source>. (<year>2021</year>) <volume>16</volume>:<fpage>457</fpage>. doi:&#xa0;<pub-id pub-id-type="doi">10.1186/s13018-021-02603-2</pub-id>
</citation>
</ref>
<ref id="B17">
<label>17</label>
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Tanaka</surname> <given-names>K</given-names>
</name>
<name>
<surname>Yamaguchi</surname> <given-names>T</given-names>
</name>
<name>
<surname>Hara</surname> <given-names>M</given-names>
</name>
</person-group>. <article-title>Iguratimod for the treatment of rheumatoid arthritis in Japan</article-title>. <source>Expert Rev Clin Immunol</source>. (<year>2015</year>) <volume>11</volume>:<page-range>565&#x2013;73</page-range>. doi:&#xa0;<pub-id pub-id-type="doi">10.1586/1744666x.2015.1027151</pub-id>
</citation>
</ref>
<ref id="B18">
<label>18</label>
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Xie</surname> <given-names>S</given-names>
</name>
<name>
<surname>Li</surname> <given-names>S</given-names>
</name>
<name>
<surname>Tian</surname> <given-names>J</given-names>
</name>
<name>
<surname>Li</surname> <given-names>F</given-names>
</name>
</person-group>. <article-title>Iguratimod as a new drug for rheumatoid arthritis: current landscape</article-title>. <source>Front Pharmacol</source>. (<year>2020</year>) <volume>11</volume>:<elocation-id>73</elocation-id>. doi:&#xa0;<pub-id pub-id-type="doi">10.3389/fphar.2020.00073</pub-id>
</citation>
</ref>
<ref id="B19">
<label>19</label>
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>True</surname> <given-names>DG</given-names>
</name>
<name>
<surname>Bryant</surname> <given-names>LR</given-names>
</name>
<name>
<surname>Harris</surname> <given-names>MD</given-names>
</name>
<name>
<surname>Bernert</surname> <given-names>RA</given-names>
</name>
</person-group>. <article-title>Clinical images: Hydroxychloroquine-associated mucocutaneous hyperpigmentation</article-title>. <source>Arthritis rheumatism</source>. (<year>2002</year>) <volume>46</volume>:<fpage>1698</fpage>. doi:&#xa0;<pub-id pub-id-type="doi">10.1002/art.10278</pub-id>
</citation>
</ref>
<ref id="B20">
<label>20</label>
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Millard</surname> <given-names>TP</given-names>
</name>
<name>
<surname>Kirk</surname> <given-names>A</given-names>
</name>
<name>
<surname>Ratnavel</surname> <given-names>R</given-names>
</name>
</person-group>. <article-title>Cutaneous hyperpigmentation during therapy with hydroxychloroquine</article-title>. <source>Clin Exp Dermatol</source>. (<year>2004</year>) <volume>29</volume>:<page-range>92&#x2013;3</page-range>. doi:&#xa0;<pub-id pub-id-type="doi">10.1111/j.1365-2230.2004.01412.x</pub-id>
</citation>
</ref>
<ref id="B21">
<label>21</label>
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Reynaert</surname> <given-names>S</given-names>
</name>
<name>
<surname>Setterfield</surname> <given-names>J</given-names>
</name>
<name>
<surname>Black</surname> <given-names>MM</given-names>
</name>
</person-group>. <article-title>Hydroxychloroquine-induced pigmentation in two patients with systemic lupus erythematosus</article-title>. <source>J Eur Acad Dermatol Venereology</source>. (<year>2006</year>) <volume>20</volume>:<page-range>487&#x2013;8</page-range>. doi:&#xa0;<pub-id pub-id-type="doi">10.1111/j.1468-3083.2006.01494.x</pub-id>
</citation>
</ref>
<ref id="B22">
<label>22</label>
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Amichai</surname> <given-names>B</given-names>
</name>
<name>
<surname>Gat</surname> <given-names>A</given-names>
</name>
<name>
<surname>Grunwald</surname> <given-names>MH</given-names>
</name>
</person-group>. <article-title>Cutaneous hyperpigmentation during therapy with hydroxychloroquine</article-title>. <source>J Clin Rheumatol</source>. (<year>2007</year>) <volume>13</volume>:<fpage>113</fpage>. doi:&#xa0;<pub-id pub-id-type="doi">10.1097/01.rhu.0000260649.36417.09</pub-id>
</citation>
</ref>
<ref id="B23">
<label>23</label>
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Melikoglu</surname> <given-names>MA</given-names>
</name>
<name>
<surname>Melikoglu</surname> <given-names>M</given-names>
</name>
<name>
<surname>Gurbuz</surname> <given-names>U</given-names>
</name>
<name>
<surname>Budak</surname> <given-names>BS</given-names>
</name>
<name>
<surname>Kacar</surname> <given-names>C</given-names>
</name>
</person-group>. <article-title>Hydroxychloroquine-induced hyperpigmentation: a case report</article-title>. <source>J Clin Pharm Ther</source>. (<year>2008</year>) <volume>33</volume>:<fpage>699</fpage>&#x2013;<lpage>701</lpage>. doi:&#xa0;<pub-id pub-id-type="doi">10.1111/jcp.2008.33.issue-6</pub-id>
</citation>
</ref>
<ref id="B24">
<label>24</label>
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Puri</surname> <given-names>PK</given-names>
</name>
<name>
<surname>Lountzis</surname> <given-names>NI</given-names>
</name>
<name>
<surname>Tyler</surname> <given-names>W</given-names>
</name>
<name>
<surname>Ferringer</surname> <given-names>T</given-names>
</name>
</person-group>. <article-title>Hydroxychloroquine-induced hyperpigmentation: the staining pattern</article-title>. <source>J cutaneous Pathol</source>. (<year>2008</year>) <volume>35</volume>:<page-range>1134&#x2013;7</page-range>. doi:&#xa0;<pub-id pub-id-type="doi">10.1111/j.1600-0560.2008.01004.x</pub-id>
</citation>
</ref>
<ref id="B25">
<label>25</label>
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Rood</surname> <given-names>MJ</given-names>
</name>
<name>
<surname>Vermeer</surname> <given-names>MH</given-names>
</name>
<name>
<surname>Huizinga</surname> <given-names>TW</given-names>
</name>
</person-group>. <article-title>Hyperpigmentation of the skin due to hydroxychloroquine</article-title>. <source>Scandinavian J Rheumatol</source>. (<year>2008</year>) <volume>37</volume>:<fpage>158</fpage>. doi:&#xa0;<pub-id pub-id-type="doi">10.1080/03009740701769735</pub-id>
</citation>
</ref>
<ref id="B26">
<label>26</label>
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Morrison</surname> <given-names>LK</given-names>
</name>
<name>
<surname>Nordlund</surname> <given-names>JJ</given-names>
</name>
<name>
<surname>Heffernan</surname> <given-names>MP</given-names>
</name>
</person-group>. <article-title>Persistent cutaneous hyperpigmentation due to hydroxychloroquinone one year after therapy discontinuation</article-title>. <source>Dermatol Online J</source>. (<year>2009</year>) <volume>15</volume>:<fpage>15</fpage>. doi:&#xa0;<pub-id pub-id-type="doi">10.5070/D32T07Q0NW</pub-id>
</citation>
</ref>
<ref id="B27">
<label>27</label>
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Cho</surname> <given-names>EB</given-names>
</name>
<name>
<surname>Kim</surname> <given-names>BC</given-names>
</name>
<name>
<surname>Park</surname> <given-names>EJ</given-names>
</name>
<name>
<surname>Kwon</surname> <given-names>IH</given-names>
</name>
<name>
<surname>Cho</surname> <given-names>HJ</given-names>
</name>
<name>
<surname>Kim</surname> <given-names>KH</given-names>
</name>
<etal/>
</person-group>. <article-title>Hydroxychloroquine-induced hyperpigmentation</article-title>. <source>J Dermatol</source>. (<year>2012</year>) <volume>39</volume>:<page-range>859&#x2013;60</page-range>. doi:&#xa0;<pub-id pub-id-type="doi">10.1111/j.1346-8138.2012.01591.x</pub-id>
</citation>
</ref>
<ref id="B28">
<label>28</label>
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Mir</surname> <given-names>A</given-names>
</name>
<name>
<surname>Boyd</surname> <given-names>KP</given-names>
</name>
<name>
<surname>Meehan</surname> <given-names>SA</given-names>
</name>
<name>
<surname>McLellan</surname> <given-names>B</given-names>
</name>
</person-group>. <article-title>Hydroxycholoroquine-induced hyperpigmentation</article-title>. <source>Dermatol Online J</source>. (<year>2013</year>) <volume>19</volume>:<fpage>20723</fpage>. doi:&#xa0;<pub-id pub-id-type="doi">10.5070/D31912020723</pub-id>
</citation>
</ref>
<ref id="B29">
<label>29</label>
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Cohen</surname> <given-names>PR</given-names>
</name>
</person-group>. <article-title>Hydroxychloroquine-associated hyperpigmentation mimicking elder abuse</article-title>. <source>Dermatol Ther</source>. (<year>2013</year>) <volume>3</volume>:<page-range>203&#x2013;10</page-range>. doi:&#xa0;<pub-id pub-id-type="doi">10.1007/s13555-013-0032-z</pub-id>
</citation>
</ref>
<ref id="B30">
<label>30</label>
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Tracy</surname> <given-names>CL</given-names>
</name>
<name>
<surname>Blakey</surname> <given-names>B</given-names>
</name>
<name>
<surname>Parker</surname> <given-names>G</given-names>
</name>
<name>
<surname>Roebuck</surname> <given-names>J</given-names>
</name>
</person-group>. <article-title>Hydroxychloroquine-induced hyperpigmentation</article-title>. <source>J Clin Rheumatol</source>. (<year>2013</year>) <volume>19</volume>:<fpage>292</fpage>. doi:&#xa0;<pub-id pub-id-type="doi">10.1097/RHU.0b013e31829d547b</pub-id>
</citation>
</ref>
<ref id="B31">
<label>31</label>
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Sawalha</surname> <given-names>AH</given-names>
</name>
</person-group>. <article-title>Hydroxychloroquine-induced hyperpigmentation of the skin</article-title>. <source>J Rheumatol</source>. (<year>2015</year>) <volume>42</volume>:<page-range>135&#x2013;6</page-range>. doi:&#xa0;<pub-id pub-id-type="doi">10.3899/jrheum.140995</pub-id>
</citation>
</ref>
<ref id="B32">
<label>32</label>
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Coulombe</surname> <given-names>J</given-names>
</name>
<name>
<surname>Boccara</surname> <given-names>O</given-names>
</name>
</person-group>. <article-title>Hydroxychloroquine-related skin discoloration</article-title>. <source>CMAJ Can Med Assoc J</source>. (<year>2017</year>) <volume>189</volume>:<elocation-id>E212</elocation-id>. doi:&#xa0;<pub-id pub-id-type="doi">10.1503/cmaj.150622</pub-id>
</citation>
</ref>
<ref id="B33">
<label>33</label>
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Ivo</surname> <given-names>R</given-names>
</name>
<name>
<surname>Lopes</surname> <given-names>CA</given-names>
</name>
<name>
<surname>Reis</surname> <given-names>R</given-names>
</name>
</person-group>. <article-title>Woman in grey: hydroxychloroquine-induced hyperpigmentation</article-title>. <source>BMJ Case Rep</source>. (<year>2018</year>) <volume>11</volume>:<page-range>1</page-range>. doi:&#xa0;<pub-id pub-id-type="doi">10.1136/bcr-2018-227305</pub-id>
</citation>
</ref>
<ref id="B34">
<label>34</label>
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Thakur</surname> <given-names>V</given-names>
</name>
<name>
<surname>Dalla</surname> <given-names>A</given-names>
</name>
<name>
<surname>Kumar</surname> <given-names>S</given-names>
</name>
<name>
<surname>Kumaran</surname> <given-names>MS</given-names>
</name>
<name>
<surname>Aggarwal</surname> <given-names>D</given-names>
</name>
<name>
<surname>Radotra</surname> <given-names>BD</given-names>
</name>
</person-group>. <article-title>Hydroxychloroquine induced cutaneous pigmentation: a unique pattern</article-title>. <source>Postgraduate Med J</source>. (<year>2019</year>) <volume>95</volume>:<page-range>169&#x2013;70</page-range>. doi:&#xa0;<pub-id pub-id-type="doi">10.1136/postgradmedj-2018-136377</pub-id>
</citation>
</ref>
<ref id="B35">
<label>35</label>
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Tosios</surname> <given-names>KI</given-names>
</name>
<name>
<surname>Kalogirou</surname> <given-names>EM</given-names>
</name>
<name>
<surname>Sklavounou</surname> <given-names>A</given-names>
</name>
</person-group>. <article-title>Drug-associated hyperpigmentation of the oral mucosa: report of four cases</article-title>. <source>Oral surgery Oral medicine Oral Pathol Oral Radiol</source>. (<year>2018</year>) <volume>125</volume>:<page-range>e54&#x2013;66</page-range>. doi:&#xa0;<pub-id pub-id-type="doi">10.1016/j.oooo.2017.10.006</pub-id>
</citation>
</ref>
<ref id="B36">
<label>36</label>
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Tekg&#xf6;z</surname> <given-names>E</given-names>
</name>
<name>
<surname>Ak&#x131;nc&#x131;o&#x11f;lu</surname> <given-names>E</given-names>
</name>
<name>
<surname>&#xc7;&#x131;nar</surname> <given-names>M</given-names>
</name>
<name>
<surname>Y&#x131;lmaz</surname> <given-names>S</given-names>
</name>
</person-group>. <article-title>A case of exogenous ochronosis associated with hydroxychloroquine</article-title>. <source>Eur J Rheumatol</source>. (<year>2018</year>) <volume>5</volume>:<page-range>206&#x2013;8</page-range>. doi:&#xa0;<pub-id pub-id-type="doi">10.5152/eurjrheum.2018.17190</pub-id>
</citation>
</ref>
<ref id="B37">
<label>37</label>
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Shearer</surname> <given-names>RV</given-names>
</name>
<name>
<surname>Dubois</surname> <given-names>EL</given-names>
</name>
</person-group>. <article-title>Ocular changes induced by long-term hydroxychloroquine (plaquenil) therapy</article-title>. <source>Am J Ophthalmol</source>. (<year>1967</year>) <volume>64</volume>:<page-range>245&#x2013;52</page-range>. doi:&#xa0;<pub-id pub-id-type="doi">10.1016/0002-9394(67)92518-4</pub-id>
</citation>
</ref>
<ref id="B38">
<label>38</label>
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Johnson</surname> <given-names>MW</given-names>
</name>
<name>
<surname>Vine</surname> <given-names>AK</given-names>
</name>
</person-group>. <article-title>Hydroxychloroquine therapy in massive total doses without retinal toxicity</article-title>. <source>Am J Ophthalmol</source>. (<year>1987</year>) <volume>104</volume>:<page-range>139&#x2013;44</page-range>. doi:&#xa0;<pub-id pub-id-type="doi">10.1016/0002-9394(87)90005-5</pub-id>
</citation>
</ref>
<ref id="B39">
<label>39</label>
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Weiner</surname> <given-names>A</given-names>
</name>
<name>
<surname>Sandberg</surname> <given-names>MA</given-names>
</name>
<name>
<surname>Gaudio</surname> <given-names>AR</given-names>
</name>
<name>
<surname>Kini</surname> <given-names>MM</given-names>
</name>
<name>
<surname>Berson</surname> <given-names>EL</given-names>
</name>
</person-group>. <article-title>Hydroxychloroquine retinopathy</article-title>. <source>Am J Ophthalmol</source>. (<year>1991</year>) <volume>112</volume>:<page-range>528&#x2013;34</page-range>. doi:&#xa0;<pub-id pub-id-type="doi">10.1016/s0002-9394(14)76853-9</pub-id>
</citation>
</ref>
<ref id="B40">
<label>40</label>
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Fung</surname> <given-names>AE</given-names>
</name>
<name>
<surname>Samy</surname> <given-names>CN</given-names>
</name>
<name>
<surname>Rosenfeld</surname> <given-names>PJ</given-names>
</name>
</person-group>. <article-title>Optical coherence tomography findings in hydroxychloroquine and chloroquine-associated maculopathy</article-title>. <source>Retinal cases Brief Rep</source>. (<year>2007</year>) <volume>1</volume>:<page-range>128&#x2013;30</page-range>. doi:&#xa0;<pub-id pub-id-type="doi">10.1097/01.iae.0000226540.61840.d7</pub-id>
</citation>
</ref>
<ref id="B41">
<label>41</label>
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Salu</surname> <given-names>P</given-names>
</name>
<name>
<surname>Uvijls</surname> <given-names>A</given-names>
</name>
<name>
<surname>van den Brande</surname> <given-names>P</given-names>
</name>
<name>
<surname>Leroy</surname> <given-names>BP</given-names>
</name>
</person-group>. <article-title>Normalization of generalized retinal function and progression of maculopathy after cessation of therapy in a case of severe hydroxychloroquine retinopathy with 19 years follow-up</article-title>. <source>Documenta ophthalmologica Adv Ophthalmol</source>. (<year>2010</year>) <volume>120</volume>:<page-range>251&#x2013;64</page-range>. doi:&#xa0;<pub-id pub-id-type="doi">10.1007/s10633-010-9220-7</pub-id>
</citation>
</ref>
<ref id="B42">
<label>42</label>
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Phillips</surname> <given-names>BN</given-names>
</name>
<name>
<surname>Chun</surname> <given-names>DW</given-names>
</name>
</person-group>. <article-title>Hydroxychloroquine retinopathy after short-term therapy</article-title>. <source>Retinal Cases Brief Rep</source>. (<year>2014</year>) <volume>8</volume>:<page-range>67&#x2013;9</page-range>. doi:&#xa0;<pub-id pub-id-type="doi">10.1097/icb.0000000000000006</pub-id>
</citation>
</ref>
<ref id="B43">
<label>43</label>
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Wong</surname> <given-names>KL</given-names>
</name>
<name>
<surname>Pautler</surname> <given-names>SE</given-names>
</name>
<name>
<surname>Browning</surname> <given-names>DJ</given-names>
</name>
</person-group>. <article-title>Near-infrared reflectance bull's eye maculopathy as an early indication of hydroxychloroquine toxicity</article-title>. <source>Clin Ophthalmol (Auckland NZ)</source>. (<year>2015</year>) <volume>9</volume>:<page-range>521&#x2013;5</page-range>. doi:&#xa0;<pub-id pub-id-type="doi">10.2147/opth.S76963</pub-id>
</citation>
</ref>
<ref id="B44">
<label>44</label>
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Brandao</surname> <given-names>LM</given-names>
</name>
<name>
<surname>Palmowski-Wolfe</surname> <given-names>AM</given-names>
</name>
</person-group>. <article-title>A possible early sign of hydroxychloroquine macular toxicity</article-title>. <source>Documenta Ophthalmologica Adv Ophthalmol</source>. (<year>2016</year>) <volume>132</volume>:<fpage>75</fpage>&#x2013;<lpage>81</lpage>. doi:&#xa0;<pub-id pub-id-type="doi">10.1007/s10633-015-9521-y</pub-id>
</citation>
</ref>
<ref id="B45">
<label>45</label>
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Modi</surname> <given-names>YS</given-names>
</name>
<name>
<surname>Singh</surname> <given-names>RP</given-names>
</name>
</person-group>. <article-title>Bull's-eye maculopathy associated with hydroxychloroquine</article-title>. <source>New Engl J Med</source>. (<year>2019</year>) <volume>380</volume>:<fpage>1656</fpage>. doi:&#xa0;<pub-id pub-id-type="doi">10.1056/NEJMicm1412167</pub-id>
</citation>
</ref>
<ref id="B46">
<label>46</label>
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Pellerano</surname> <given-names>F</given-names>
</name>
<name>
<surname>Chah&#xed;n</surname> <given-names>G</given-names>
</name>
<name>
<surname>Niurka Leonor</surname> <given-names>M</given-names>
</name>
<name>
<surname>Stern</surname> <given-names>H</given-names>
</name>
</person-group>. <article-title>Hydroxychloroquine-induced bull's eye maculopathy</article-title>. <source>Lancet Rheumatol</source>. (<year>2020</year>) <volume>2</volume>:<elocation-id>e120</elocation-id>. doi:&#xa0;<pub-id pub-id-type="doi">10.1016/s2665-9913(19)30040-2</pub-id>
</citation>
</ref>
<ref id="B47">
<label>47</label>
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Ameen Ismail</surname> <given-names>A</given-names>
</name>
<name>
<surname>Sadek</surname> <given-names>SH</given-names>
</name>
<name>
<surname>Hatata</surname> <given-names>RM</given-names>
</name>
</person-group>. <article-title>Early onset monocular hydroxychloroquine maculopathy in a systemic lupus erythematosus patient with history of central retinal artery occlusion: a case report</article-title>. <source>BMC Ophthalmol</source>. (<year>2022</year>) <volume>22</volume>:<fpage>434</fpage>. doi:&#xa0;<pub-id pub-id-type="doi">10.1186/s12886-022-02657-8</pub-id>
</citation>
</ref>
<ref id="B48">
<label>48</label>
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Lippard</surname> <given-names>VW</given-names>
</name>
<name>
<surname>Kauer</surname> <given-names>GL</given-names>
<suffix>Jr</suffix>
</name>
</person-group>. <article-title>Pigmentation of the palate and subungual tissues associated with suppressive quinacrine hydrochloride therapy</article-title>. <source>Am J Trop Med hygiene</source>. (<year>1945</year>) <volume>25</volume>:<page-range>469&#x2013;71</page-range>. doi:&#xa0;<pub-id pub-id-type="doi">10.4269/ajtmh.1945.s1-25.469</pub-id>
</citation>
</ref>
<ref id="B49">
<label>49</label>
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Skare</surname> <given-names>T</given-names>
</name>
<name>
<surname>Ribeiro</surname> <given-names>CF</given-names>
</name>
<name>
<surname>Souza</surname> <given-names>FH</given-names>
</name>
<name>
<surname>Haendchen</surname> <given-names>L</given-names>
</name>
<name>
<surname>Jord&#xe3;o</surname> <given-names>JM</given-names>
</name>
</person-group>. <article-title>Antimalarial cutaneous side effects: a study in 209 users</article-title>. <source>Cutaneous Ocular Toxicol</source>. (<year>2011</year>) <volume>30</volume>:<page-range>45&#x2013;9</page-range>. doi:&#xa0;<pub-id pub-id-type="doi">10.3109/15569527.2010.521225</pub-id>
</citation>
</ref>
<ref id="B50">
<label>50</label>
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Jallouli</surname> <given-names>M</given-names>
</name>
<name>
<surname>Franc&#xe8;s</surname> <given-names>C</given-names>
</name>
<name>
<surname>Piette</surname> <given-names>JC</given-names>
</name>
<name>
<surname>Huong du</surname> <given-names>LT</given-names>
</name>
<name>
<surname>Moguelet</surname> <given-names>P</given-names>
</name>
<name>
<surname>Factor</surname> <given-names>C</given-names>
</name>
<etal/>
</person-group>. <article-title>Hydroxychloroquine-induced pigmentation in patients with systemic lupus erythematosus: a case-control study</article-title>. <source>JAMA Dermatol</source>. (<year>2013</year>) <volume>149</volume>:<page-range>935&#x2013;40</page-range>. doi:&#xa0;<pub-id pub-id-type="doi">10.1001/jamadermatol.2013.709</pub-id>
</citation>
</ref>
<ref id="B51">
<label>51</label>
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Melles</surname> <given-names>RB</given-names>
</name>
<name>
<surname>Marmor</surname> <given-names>MF</given-names>
</name>
</person-group>. <article-title>The risk of toxic retinopathy in patients on long-term hydroxychloroquine therapy</article-title>. <source>JAMA Ophthalmol</source>. (<year>2014</year>) <volume>132</volume>:<page-range>1453&#x2013;60</page-range>. doi:&#xa0;<pub-id pub-id-type="doi">10.1001/jamaophthalmol.2014.3459</pub-id>
</citation>
</ref>
<ref id="B52">
<label>52</label>
<citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Hallali</surname> <given-names>G</given-names>
</name>
<name>
<surname>Seyed</surname> <given-names>Z</given-names>
</name>
<name>
<surname>Maillard</surname> <given-names>AV</given-names>
</name>
<name>
<surname>Drine</surname> <given-names>K</given-names>
</name>
<name>
<surname>Lamour</surname> <given-names>L</given-names>
</name>
<name>
<surname>Faure</surname> <given-names>C</given-names>
</name>
<etal/>
</person-group>. <article-title>Extreme interocular asymmetry in an atypical case of a hydroxychloroquine-related retinopathy</article-title>. <source>Medicina (Kaunas Lithuania)</source>. (<year>2022</year>) <volume>58</volume>:<page-range>1</page-range>. doi:&#xa0;<pub-id pub-id-type="doi">10.3390/medicina58070967</pub-id>
</citation>
</ref>
</ref-list>
</back>
</article>