International Journal of Rheumatic Diseases 2014
CORRESPONDENCE
Improvement of vitiligo in a patient with rheumatoid arthritis after hydroxychloroquine treatment Dear Editor, Antimalarial agents are one of the most commonly prescribed drugs for the treatment of autoimmune diseases, including rheumatoid arthritis (RA). Hydroxychloroquine (HCQ) has long-term treatment benefits in RA. Recent data suggest that HCQ may have more wide-reaching medical implications, including diabetes mellitus, dyslipidemias, infectious diseases, coagulopathies and malignancies,1 but HCQ has also been reported to cause pigmentary changes in approximately 10–25% of patients.2 Here, we present a case of vitiligo in a patient with RA that improved following HCQ treatment. A 39-year-old woman presented in December 2010 with a 3-months history of multiple joint pain. Physical examination showed tenderness and swelling in several joints. Laboratory findings were positive for anti-cyclic citrullinated peptide antibody and anti-Ro antibody, but negative for rheumatoid factor and anti-nuclear antibody. Erythrocyte sedimentation rate and C-reactive (a)
(b)
(c)
(d)
protein level were elevated to 35 mm/h and 0.64 mg/ dL, respectively. Serum thyroid-stimulating hormone and free T4 levels were normal. Bone scintigraphy showed increased uptake in both the wrists and small joints of the right hand. Chest computed tomography showed mild ground-glass opacity in the peribronchovascular and subpleural areas. She was diagnosed with seropositive RA and interstitial lung disease. The patient had a 20-year history of vitiligo on the face, trunk and extremities. Before RA diagnosis, she was treated with ultraviolet light (UV) for 6 months and experienced improvement of facial vitiligo. She reported no change in other areas of her body. In May 2011, HCQ (200 mg daily) and methotrexate (MTX) (7.5 mg weekly) were prescribed for the treatment of her RA. Glucocorticoids were not prescribed. HCQ was discontinued from September 2011 to November 2011 because of the patient’s wish due to improvement in her arthritis. The patient revisited the rheumatology clinic in December 2011 with worsening
Figure 1 Vitiligo before (a, b) and after (c, d) treatment with hydroxychloroquine.
© 2014 Asia Pacific League of Associations for Rheumatology and Wiley Publishing Asia Pty Ltd
Correspondence
of her arthritis and HCQ was restarted at 200 mg daily, increased to 300 mg daily in August 2012 and to 400 mg daily in June 2013. Vitiligo improved on her hands and wrists 4 months after starting HCQ, worsened during the period when the HCQ was discontinued and continued to improve after restarting HCQ treatment (Fig. 1). The patient reported that she discontinued the weekly dose of MTX since the first prescription. Ophthalmic examination has shown no signs of retinopathy. She is receiving a steady dose of HCQ (400 mg daily) and no side-effects have been noted. Several case reports of hyperpigmentation following HCQ treatment in RA patients have been published.3–5 However, the exact mechanism of hyperpigmentation is unknown. HCQ inhibits the action of acidic proteases involved in many cellular functions, such as toll-like receptor signaling, antigen presentation, and the production of proinflammatory and anti-inflammatory cytokines, such as tumor necrosis factor (TNF)-a. The etiology of vitiligo remains unknown. The melanocytotoxicity of CD4+ T cells, reactivity of CD8+ T cells, absence of regulatory T cells and overexpression of several cytokines have previously been suggested as possible immunopathogenetic factors of autoimmune vitiligo.6 Recently, Laddha et al.7 reported that TNF-a promotor polymorphisms may be genetic risk factors for susceptibility and progression of vitiligo. The upregulation of TNF-a transcript and protein levels in individuals with susceptible haplotypes advocates a crucial role of TNF-a in the autoimmune pathogenesis of vitiligo, and since HCQ inhibits TNF-a production, this could be a mechanism involved in the improvement of vitiligo in RA patients. In a study investigating the prevalence and distribution of autoimmune diseases (AD) in 368 families, the investigators reported that the most common AD among relatives of patients with RA were autoimmune thyroid diseases and vitiligo.8 The current standard therapy for vitiligo is UV light and topical agents (corticosteroids and calcineurin inhibitors). Other treatment options include camouflaging or depigmentation treatments. MTX is an effective treatment for vitiligo, but our patient showed poor compliance to weekly MTX and MTX was stopped. When HCQ was discontinued, the patient’s vitiligo worsened, which suggests that HCQ played a role in the improvement of vitiligo. To our knowledge, this is the first case report of vitiligo that improved after HCQ treatment in a patient
2
with RA. Here, we suggest that repigmentation therapy using HCQ could have added benefits in RA patients with vitiligo.
ACKNOWLEDGEMENTS This work was supported by INHA UNIVERSITY Research Grant.
CONFLICT OF INTEREST The authors have no conflicts of interest to disclose. Kowoon JOO, Won PARK, Seong Ryul KWON, Mie Jin LIM and Kyong-Hee JUNG
Division of Rheumatology, Department of Internal Medicine, Inha University Hospital, Incheon, Korea Correspondence: Professor Kyong-Hee Jung, email: [email protected]
REFERENCES 1 Olsen NJ, Schleich MA, Karp DR (2013) Multifaceted effects of hydroxychloroquine in human disease. Semin Arthritis Rheum 43, 264–72. 2 Millard TP, Kirk A, Ratnavel R (2004) Cutaneous hyperpigmentation during therapy with hydroxychloroquine. Clin Exp Dermatol 29, 923. 3 Amichai B, Gat A, Grunwald MH (2007) Cutaneous hyperpigmentation during therapy with hydroxychloroquine. J Clin Rheumatol 13, 113. 4 Cho EB, Kim BC, Park EJ et al. (2012) Hydroxychloroquine-induced hyperpigmentation. J Dermatol 39, 859–60. 5 Rood MJ, Vermeer MH, Huizinga TW (2008) Hyperpigmentation of the skin due to hydroxychloroquine. Scand J Rheumatol 37, 158. 6 Sandoval-Cruz M, Garcıa-Carrasco M, Sanchez-Porras R et al. (2011) Immunopathogenesis of vitiligo. Autoimmun Rev 10, 762–5. 7 Laddha NC, Dwivedi M, Begum R (2012) Increased tumor necrosis factor (TNF)-a and its promoter polymorphisms correlate with disease progression and higher susceptibility towards vitiligo. PLoS ONE 7, e52298. 8 Michou L, Rat AC, Lasbleiz S, Bardin T, Cornelis F (2008) Prevalence and distribution of autoimmune diseases in 368 rheumatoid arthritis families. J Rheumatol 35, 790–6.
International Journal of Rheumatic Diseases 2014
CORRESPONDENCE
Improvement of vitiligo in a patient with rheumatoid arthritis after hydroxychloroquine treatment Dear Editor, Antimalarial agents are one of the most commonly prescribed drugs for the treatment of autoimmune diseases, including rheumatoid arthritis (RA). Hydroxychloroquine (HCQ) has long-term treatment benefits in RA. Recent data suggest that HCQ may have more wide-reaching medical implications, including diabetes mellitus, dyslipidemias, infectious diseases, coagulopathies and malignancies,1 but HCQ has also been reported to cause pigmentary changes in approximately 10–25% of patients.2 Here, we present a case of vitiligo in a patient with RA that improved following HCQ treatment. A 39-year-old woman presented in December 2010 with a 3-months history of multiple joint pain. Physical examination showed tenderness and swelling in several joints. Laboratory findings were positive for anti-cyclic citrullinated peptide antibody and anti-Ro antibody, but negative for rheumatoid factor and anti-nuclear antibody. Erythrocyte sedimentation rate and C-reactive (a)
(b)
(c)
(d)
protein level were elevated to 35 mm/h and 0.64 mg/ dL, respectively. Serum thyroid-stimulating hormone and free T4 levels were normal. Bone scintigraphy showed increased uptake in both the wrists and small joints of the right hand. Chest computed tomography showed mild ground-glass opacity in the peribronchovascular and subpleural areas. She was diagnosed with seropositive RA and interstitial lung disease. The patient had a 20-year history of vitiligo on the face, trunk and extremities. Before RA diagnosis, she was treated with ultraviolet light (UV) for 6 months and experienced improvement of facial vitiligo. She reported no change in other areas of her body. In May 2011, HCQ (200 mg daily) and methotrexate (MTX) (7.5 mg weekly) were prescribed for the treatment of her RA. Glucocorticoids were not prescribed. HCQ was discontinued from September 2011 to November 2011 because of the patient’s wish due to improvement in her arthritis. The patient revisited the rheumatology clinic in December 2011 with worsening
Figure 1 Vitiligo before (a, b) and after (c, d) treatment with hydroxychloroquine.
© 2014 Asia Pacific League of Associations for Rheumatology and Wiley Publishing Asia Pty Ltd
Correspondence
of her arthritis and HCQ was restarted at 200 mg daily, increased to 300 mg daily in August 2012 and to 400 mg daily in June 2013. Vitiligo improved on her hands and wrists 4 months after starting HCQ, worsened during the period when the HCQ was discontinued and continued to improve after restarting HCQ treatment (Fig. 1). The patient reported that she discontinued the weekly dose of MTX since the first prescription. Ophthalmic examination has shown no signs of retinopathy. She is receiving a steady dose of HCQ (400 mg daily) and no side-effects have been noted. Several case reports of hyperpigmentation following HCQ treatment in RA patients have been published.3–5 However, the exact mechanism of hyperpigmentation is unknown. HCQ inhibits the action of acidic proteases involved in many cellular functions, such as toll-like receptor signaling, antigen presentation, and the production of proinflammatory and anti-inflammatory cytokines, such as tumor necrosis factor (TNF)-a. The etiology of vitiligo remains unknown. The melanocytotoxicity of CD4+ T cells, reactivity of CD8+ T cells, absence of regulatory T cells and overexpression of several cytokines have previously been suggested as possible immunopathogenetic factors of autoimmune vitiligo.6 Recently, Laddha et al.7 reported that TNF-a promotor polymorphisms may be genetic risk factors for susceptibility and progression of vitiligo. The upregulation of TNF-a transcript and protein levels in individuals with susceptible haplotypes advocates a crucial role of TNF-a in the autoimmune pathogenesis of vitiligo, and since HCQ inhibits TNF-a production, this could be a mechanism involved in the improvement of vitiligo in RA patients. In a study investigating the prevalence and distribution of autoimmune diseases (AD) in 368 families, the investigators reported that the most common AD among relatives of patients with RA were autoimmune thyroid diseases and vitiligo.8 The current standard therapy for vitiligo is UV light and topical agents (corticosteroids and calcineurin inhibitors). Other treatment options include camouflaging or depigmentation treatments. MTX is an effective treatment for vitiligo, but our patient showed poor compliance to weekly MTX and MTX was stopped. When HCQ was discontinued, the patient’s vitiligo worsened, which suggests that HCQ played a role in the improvement of vitiligo. To our knowledge, this is the first case report of vitiligo that improved after HCQ treatment in a patient
2
with RA. Here, we suggest that repigmentation therapy using HCQ could have added benefits in RA patients with vitiligo.
ACKNOWLEDGEMENTS This work was supported by INHA UNIVERSITY Research Grant.
CONFLICT OF INTEREST The authors have no conflicts of interest to disclose. Kowoon JOO, Won PARK, Seong Ryul KWON, Mie Jin LIM and Kyong-Hee JUNG
Division of Rheumatology, Department of Internal Medicine, Inha University Hospital, Incheon, Korea Correspondence: Professor Kyong-Hee Jung, email: [email protected]
REFERENCES 1 Olsen NJ, Schleich MA, Karp DR (2013) Multifaceted effects of hydroxychloroquine in human disease. Semin Arthritis Rheum 43, 264–72. 2 Millard TP, Kirk A, Ratnavel R (2004) Cutaneous hyperpigmentation during therapy with hydroxychloroquine. Clin Exp Dermatol 29, 923. 3 Amichai B, Gat A, Grunwald MH (2007) Cutaneous hyperpigmentation during therapy with hydroxychloroquine. J Clin Rheumatol 13, 113. 4 Cho EB, Kim BC, Park EJ et al. (2012) Hydroxychloroquine-induced hyperpigmentation. J Dermatol 39, 859–60. 5 Rood MJ, Vermeer MH, Huizinga TW (2008) Hyperpigmentation of the skin due to hydroxychloroquine. Scand J Rheumatol 37, 158. 6 Sandoval-Cruz M, Garcıa-Carrasco M, Sanchez-Porras R et al. (2011) Immunopathogenesis of vitiligo. Autoimmun Rev 10, 762–5. 7 Laddha NC, Dwivedi M, Begum R (2012) Increased tumor necrosis factor (TNF)-a and its promoter polymorphisms correlate with disease progression and higher susceptibility towards vitiligo. PLoS ONE 7, e52298. 8 Michou L, Rat AC, Lasbleiz S, Bardin T, Cornelis F (2008) Prevalence and distribution of autoimmune diseases in 368 rheumatoid arthritis families. J Rheumatol 35, 790–6.
International Journal of Rheumatic Diseases 2014
