Case and research letter
Oral Hyperpigmentation Associated With Interferon-Alpha and Ribavirin Therapy for Hepatitis C Virus Infection
Pigmentación oral asociada al tratamiento con alfa-interferón y ribavirina para la hepatitis C
J. Marcoval
, J. Notario, C. Martín, S. Gómez
Corresponding author
Servicio de Dermatología, Hospital Universitari de Bellvitge, IDIBELL, Barcelona, Spain
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B, Drainage of yellowish material after puncture.</p>" ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "C. Fischer-Levancini, M. Iglesias-Sancho, H. Collgros, M. Sánchez-Regaña." "autores" => array:4 [ 0 => array:2 [ "nombre" => "C." "apellidos" => "Fischer-Levancini" ] 1 => array:2 [ "nombre" => "M." "apellidos" => "Iglesias-Sancho" ] 2 => array:2 [ "nombre" => "H." "apellidos" => "Collgros" ] 3 => array:2 [ "nombre" => "M." 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Marcoval, J. Notario, C. Martín, S. Gómez" "autores" => array:4 [ 0 => array:4 [ "nombre" => "J." "apellidos" => "Marcoval" "email" => array:1 [ 0 => "jmarcoval@bellvitgehospital.cat" ] "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">¿</span>" "identificador" => "cor0005" ] ] ] 1 => array:2 [ "nombre" => "J." "apellidos" => "Notario" ] 2 => array:2 [ "nombre" => "C." "apellidos" => "Martín" ] 3 => array:2 [ "nombre" => "S." "apellidos" => "Gómez" ] ] "afiliaciones" => array:1 [ 0 => array:2 [ "entidad" => "Servicio de Dermatología, Hospital Universitari de Bellvitge, IDIBELL, Barcelona, Spain" "identificador" => "aff0005" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Pigmentación oral asociada al tratamiento con alfa-interferón y ribavirina para la hepatitis <span class="elsevierStyleSmallCaps">C</span>" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0010" "etiqueta" => "Figure 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 600 "Ancho" => 900 "Tamanyo" => 61170 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Pigmentation of the left cheek mucosa.</p>" ] ] ] "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall">Since 2003, there have been reports of oral hyperpigmentation associated with interferon alfa and ribavirin therapy for hepatitis C. We report a new case of oral pigmentation associated with this therapy in a white woman who also developed genital mucosal lesions. The patient was 49 years old and had a history of allergy to acetylsalicylic acid, depressive disorder, and chronic hepatitis C genotype 1 infection, diagnosed in 2007. In May 2008, she started treatment with pegylated interferon alfa and ribavirin with suboptimal therapeutic adherence until November 2009. The virus was not eradicated. In June 2010, the patient presented with leukocytoclastic vasculitis and arthralgia associated with cryoglobulinemia, and received treatment with colchicine and pulses of oral prednisone. From April 2011, she underwent 5 sessions of plasmapheresis and treatment with pegylated interferon alfa (180<span class="elsevierStyleHsp" style=""></span>μg/week) and ribavirin (1000<span class="elsevierStyleHsp" style=""></span>mg/d) was restarted. In July 2011, she received treatment with rituximab (2 doses) with resolution of the leukocytoclastic vasculitis. In April 2011, 1 month after the start of the second course of pegylated interferon alfa and ribavirin, the patient presented with a burning sensation on the tongue and noted pigmentation of the oral and genital mucosa. In the examination, pigmented grey-blue macules were seen located mainly on the lateral areas of the dorsum of the tongue (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>). Pigmentation was also observed on both cheek mucosae (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>) and similar lesions were detected on the vulvar mucosa. The patient did not have any hyperpigmented cutaneous lesions, and no systemic symptoms were apparent at the time. Withdrawal of treatment was not required and the lesions have remained stable until present, despite continuing with treatment.</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><elsevierMultimedia ident="fig0010"></elsevierMultimedia><p id="par0010" class="elsevierStylePara elsevierViewall">Hyperpigmentation of oral mucosa associated with interferon alfa and ribavirin combination therapy for hepatitis C was first described by Willems et al.<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> in 2003. Since then, 20 cases of patients with pigmentation of oral mucosa associated with interferon alfa and ribavirin therapy have been reported, including the present case (13 women and 7 men in total).<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1–9</span></a> Only 6 of the 20 cases reported correspond to white patients. The first 2 cases were caused by nonpegylated interferon alfa whereas the remaining cases were associated with the pegylated formulation. The lesions appeared between 1 and 11 months after starting treatment. In 7 of the 20 cases (the present case included), the patients reported subjective symptoms.<a class="elsevierStyleCrossRefs" href="#bib0015"><span class="elsevierStyleSup">3,6–9</span></a> All cases had pigmented grey-blue macules on the lingual mucosa and most were located predominantly on lateral areas of the dorsum of the tongue. Four patients had lesions in other areas of the oral mucosa. In 5 cases, hyperpigmented cutaneous lesions were present.<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1–9</span></a> The presence of vulvar pigmentation has only been reported in our patient.</p><p id="par0015" class="elsevierStylePara elsevierViewall">The development of lingual pigmentation during treatment with interferon alfa and ribavirin is not associated with any specific genotype of hepatitis virus C, dose or duration of interferon or ribavirin treatment, or response to treatment.<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> Pigmentation usually increases up to the end of treatment and tends to partially resolve after discontinuation of treatment.<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2,8</span></a> However, there are no reports of complete resolution of lesions in the long-term. Although oral lesions may cause subjective discomfort, this is not severe and it is not recommended to discontinue treatment.<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">With regard to the pathogenesis, given that interferons are able to upregulate expression of melanocyte stimulating hormone (MSH) receptors in melanocytes, Willems et al.<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> suggest that interferon alfa may have been responsible for the lingual pigmentation through an increase in melanin production in the presence of MSH. It has also been suggested that pegylated interferon alfa, with a longer half-life, might increase the risk of developing oral pigmentation.<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> In addition, the combination of interferon alfa with ribavirin has been associated with more adverse cutaneous reactions than administration of interferon alfa alone.<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a> These reactions are predominantly of the lichenoid type, suggesting a synergistic effect between the 2 drugs when inducing cutaneous side effects. The histologic image described by Willems et al.,<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> with presence of pigmentary incontinence, does not rule out a probable prior lichenoid reaction, which could be another possible pathogenic mechanism. Given that postinflammatory hyperpigmentation is more frequent in dark-skinned individuals, this may explain why lesions are more common in such individuals.<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a></p><p id="par0025" class="elsevierStylePara elsevierViewall">Although they appear more often in individuals with more darkly pigmented skin, lingual pigmentation due to interferon alfa and ribavirin has also been reported in white patients. This adverse reaction can be alarming for patients. Thus, candidates for interferon alfa and ribavirin therapy should be informed of the possibility of developing this type of lesion before starting treatment.</p></span>" "pdfFichero" => "main.pdf" "tienePdf" => true "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as: Marcoval J, Notario J, Martín C, Gómez S. Pigmentación oral asociada al tratamiento con alfa-interferón y ribavirina para la hepatitis <span class="elsevierStyleSmallCaps">C</span>. Actas Dermosifiliogr. 2014;105:211–212.</p>" ] ] "multimedia" => array:2 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 597 "Ancho" => 900 "Tamanyo" => 101820 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Pigmented grey-blue macules, located mainly on the lateral areas of the dorsum of the tongue.</p>" ] ] 1 => array:7 [ "identificador" => "fig0010" "etiqueta" => "Figure 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 600 "Ancho" => 900 "Tamanyo" => 61170 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Pigmentation of the left cheek mucosa.</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:10 [ 0 => array:3 [ "identificador" => "bib0005" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Hyperpigmentation during interferon-alpha therapy for chronic hepatitis C virus infection" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "M. 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Ogutlu" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1111/j.1346-8138.2010.01022.x" "Revista" => array:7 [ "tituloSerie" => "J Dermatol" "fecha" => "2011" "volumen" => "38" "paginaInicial" => "290" "paginaFinal" => "291" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/21342236" "web" => "Medline" ] ] "itemHostRev" => array:3 [ "pii" => "S0140673600028166" "estado" => "S300" "issn" => "01406736" ] ] ] ] ] ] ] 7 => array:3 [ "identificador" => "bib0040" "etiqueta" => "8" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Tongue hyperpigmentation resulting from peginterferon alfa-2b and ribavirin treatment in a patient with chronic hepatitis C" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "S. Ghosh" 1 => "A. Duseja" 2 => "R.K. Dhiman" 3 => "Y.K. Chawla" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1007/s10620-011-1914-5" "Revista" => array:7 [ "tituloSerie" => "Dig Dis Sci" "fecha" => "2012" "volumen" => "57" "paginaInicial" => "820" "paginaFinal" => "821" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/21948358" "web" => "Medline" ] ] "itemHostRev" => array:3 [ "pii" => "S0735109709024991" "estado" => "S300" "issn" => "07351097" ] ] ] ] ] ] ] 8 => array:3 [ "identificador" => "bib0045" "etiqueta" => "9" "referencia" => array:1 [ 0 => array:1 [ "referenciaCompleta" => "Mlika RB, Kerkeni N, Marrak H, Fenniche S, Mokhtar I, Debbiche A. Tongue hyperpigmentation during PEG-interferon-alfa/ribavirin therapy in a non-Caucasian patient with chronic hepatitis C: A case report and review of the literature. Int J Dermatol. En prensa 2012. doi: 10.1111/j.1365-4632.2011.04921.x." ] ] ] 9 => array:3 [ "identificador" => "bib0050" "etiqueta" => "10" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "High prevalence of cutaneous reactions to interferon alfa plus ribavirin combination therapy in patients with chronic hepatitis C virus" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "S. Sookoian" 1 => "V. Neglia" 2 => "G. Castaño" 3 => "B. Frider" 4 => "M.C. Kien" 5 => "E. Chohuela" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:7 [ "tituloSerie" => "Arch Dermatol" "fecha" => "1999" "volumen" => "135" "paginaInicial" => "1000" "paginaFinal" => "1001" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/10456365" "web" => "Medline" ] ] "itemHostRev" => array:3 [ "pii" => "S0735109708026260" "estado" => "S300" "issn" => "07351097" ] ] ] ] ] ] ] ] ] ] ] ] "idiomaDefecto" => "en" "url" => "/15782190/0000010500000002/v1_201403090058/S1578219014000055/v1_201403090058/en/main.assets" "Apartado" => array:4 [ "identificador" => "6157" "tipo" => "SECCION" "en" => array:2 [ "titulo" => "Case and Research Letters" "idiomaDefecto" => true ] "idiomaDefecto" => "en" ] "PDF" => "https://static.elsevier.es/multimedia/15782190/0000010500000002/v1_201403090058/S1578219014000055/v1_201403090058/en/main.pdf?idApp=UINPBA000044&text.app=https://actasdermo.org/" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S1578219014000055?idApp=UINPBA000044" ]
| Year/Month | Html | Total | |
|---|---|---|---|
| 2024 November | 12 | 14 | 26 |
| 2024 October | 115 | 59 | 174 |
| 2024 September | 76 | 35 | 111 |
| 2024 August | 107 | 84 | 191 |
| 2024 July | 77 | 36 | 113 |
| 2024 June | 74 | 29 | 103 |
| 2024 May | 73 | 37 | 110 |
| 2024 April | 85 | 24 | 109 |
| 2024 March | 86 | 31 | 117 |
| 2024 February | 72 | 27 | 99 |
| 2024 January | 63 | 36 | 99 |
| 2023 December | 46 | 20 | 66 |
| 2023 November | 60 | 30 | 90 |
| 2023 October | 68 | 33 | 101 |
| 2023 September | 64 | 43 | 107 |
| 2023 August | 59 | 22 | 81 |
| 2023 July | 75 | 32 | 107 |
| 2023 June | 50 | 26 | 76 |
| 2023 May | 68 | 20 | 88 |
| 2023 April | 49 | 25 | 74 |
| 2023 March | 49 | 25 | 74 |
| 2023 February | 55 | 20 | 75 |
| 2023 January | 53 | 39 | 92 |
| 2022 December | 67 | 42 | 109 |
| 2022 November | 35 | 26 | 61 |
| 2022 October | 40 | 20 | 60 |
| 2022 September | 30 | 40 | 70 |
| 2022 August | 17 | 34 | 51 |
| 2022 July | 23 | 30 | 53 |
| 2022 June | 28 | 29 | 57 |
| 2022 May | 49 | 29 | 78 |
| 2022 April | 78 | 31 | 109 |
| 2022 March | 100 | 40 | 140 |
| 2022 February | 43 | 18 | 61 |
| 2022 January | 48 | 31 | 79 |
| 2021 December | 52 | 33 | 85 |
| 2021 November | 56 | 41 | 97 |
| 2021 October | 66 | 48 | 114 |
| 2021 September | 48 | 40 | 88 |
| 2021 August | 52 | 28 | 80 |
| 2021 July | 47 | 26 | 73 |
| 2021 June | 45 | 28 | 73 |
| 2021 May | 43 | 38 | 81 |
| 2021 April | 70 | 26 | 96 |
| 2021 March | 57 | 22 | 79 |
| 2021 February | 57 | 16 | 73 |
| 2021 January | 37 | 10 | 47 |
| 2020 December | 38 | 14 | 52 |
| 2020 November | 20 | 8 | 28 |
| 2020 October | 28 | 10 | 38 |
| 2020 September | 32 | 15 | 47 |
| 2020 August | 17 | 10 | 27 |
| 2020 July | 35 | 10 | 45 |
| 2020 June | 26 | 18 | 44 |
| 2020 May | 20 | 12 | 32 |
| 2020 April | 32 | 19 | 51 |
| 2020 March | 29 | 23 | 52 |
| 2020 February | 3 | 6 | 9 |
| 2020 January | 2 | 12 | 14 |
| 2019 December | 8 | 1 | 9 |
| 2019 November | 4 | 0 | 4 |
| 2019 September | 8 | 1 | 9 |
| 2019 August | 2 | 1 | 3 |
| 2019 July | 6 | 10 | 16 |
| 2019 June | 6 | 14 | 20 |
| 2019 May | 5 | 17 | 22 |
| 2019 April | 2 | 19 | 21 |
| 2019 March | 2 | 8 | 10 |
| 2019 February | 6 | 0 | 6 |
| 2019 January | 2 | 3 | 5 |
| 2018 December | 0 | 3 | 3 |
| 2018 November | 2 | 4 | 6 |
| 2018 October | 3 | 0 | 3 |
| 2018 September | 5 | 3 | 8 |
| 2018 May | 0 | 1 | 1 |
| 2018 March | 28 | 1 | 29 |
| 2018 February | 95 | 5 | 100 |
| 2018 January | 126 | 2 | 128 |
| 2017 December | 89 | 5 | 94 |
| 2017 November | 65 | 10 | 75 |
| 2017 October | 58 | 3 | 61 |
| 2017 September | 62 | 5 | 67 |
| 2017 August | 91 | 9 | 100 |
| 2017 July | 67 | 7 | 74 |
| 2017 June | 82 | 22 | 104 |
| 2017 May | 83 | 16 | 99 |
| 2017 April | 116 | 8 | 124 |
| 2017 March | 81 | 23 | 104 |
| 2017 February | 70 | 19 | 89 |
| 2017 January | 53 | 5 | 58 |
| 2016 December | 65 | 13 | 78 |
| 2016 November | 117 | 6 | 123 |
| 2016 October | 116 | 11 | 127 |
| 2016 September | 187 | 9 | 196 |
| 2016 August | 161 | 8 | 169 |
| 2016 July | 71 | 7 | 78 |
| 2016 June | 15 | 4 | 19 |
| 2016 May | 6 | 5 | 11 |
| 2016 April | 6 | 16 | 22 |
| 2016 March | 3 | 22 | 25 |
| 2016 February | 7 | 18 | 25 |
| 2016 January | 13 | 14 | 27 |
| 2015 December | 3 | 13 | 16 |
| 2015 November | 8 | 12 | 20 |
| 2015 October | 8 | 4 | 12 |
| 2015 September | 6 | 41 | 47 |
| 2015 August | 4 | 2 | 6 |
| 2015 July | 130 | 11 | 141 |
| 2015 June | 60 | 1 | 61 |
| 2015 May | 60 | 4 | 64 |
| 2015 April | 62 | 12 | 74 |
| 2015 March | 76 | 3 | 79 |
| 2015 February | 60 | 4 | 64 |
| 2015 January | 54 | 1 | 55 |
| 2014 December | 54 | 4 | 58 |
| 2014 November | 48 | 4 | 52 |
| 2014 October | 40 | 3 | 43 |
| 2014 September | 43 | 1 | 44 |
| 2014 August | 36 | 8 | 44 |
| 2014 July | 33 | 5 | 38 |
| 2014 June | 42 | 4 | 46 |
| 2014 May | 34 | 6 | 40 |
| 2014 April | 14 | 3 | 17 |
| 2014 March | 20 | 5 | 25 |
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