CED
Clinical dermatology • Concise report
Clinical and Experimental Dermatology
Multiple halo naevi associated with tocilizumab K. Kuet and M. Goodfield Department of Dermatology, Chapel Allerton Hospital, Leeds, West Yorkshire, UK doi:10.1111/ced.12385
Summary
Tocilizumab, a humanized monoclonal antibody directed against the interleukin (IL)-6 receptor, is approved for the treatment of rheumatoid arthritis and juvenile idiopathic arthritis (JIA). We describe a case of multiple halo naevi occurring in a patient with a history of JIA treated with tocilizumab. IL-6 is a key cytokine in the setting of cancer through its effects on angiogenesis and inhibition of adaptive antitumour immunity. IL-6 also plays a role in melanocyte function, and increased levels have been noted in vitiligo skin, where it is a paracrine inhibitor of melanocytes. Tocilizumab may therefore lead to the development of halo naevi secondary to subsequent activation of adaptive immunity. Alternatively, as tocilizumab results in increased serum IL-6 levels, the epidermal cytokine profile is altered. Increased levels of IL-6 may therefore have a direct inhibitory effect on melanocytes, where access by tocilizumab may be limited due to differential size difference.
Tocilizumab, a humanized monoclonal antibody against the interleukin-6 (IL-6) receptor, is licensed for the treatment of rheumatoid arthritis (RA) and systemic juvenile idiopathic arthritis (JIA).1 Tocilizumab reduces joint inflammation, thereby preventing longterm damage and producing improvement in quality of life and function. Reported adverse effects include abnormal liver function tests, transient neutropenia, increase in lipids, and infections due to its immunomodulatory effects.
Report A 33-year-old woman presented with an 8-month history of gradual hypopigmentation affecting all her longstanding moles, and the appearance of a pale rim surrounding every mole. She had a history of discoid eczema, migraines and seropositive JIA since the age of 4 years. Over the 3 years prior to this presentation, her arthritis had been well controlled with tocilizumab (8 mg/kg once every 2 weeks), having previously Correspondence: Dr Kar Hung Kuet, Department of Dermatology, Royal Hallamshire Hospital, Glossop Road, Sheffield, S10 2JF, UK E-mail: [email protected] Conflict of interest: the authors declare that they have no conflicts of interest. Accepted for publication 4 February 2014
ª 2014 British Association of Dermatologists
failed a number of anti-tumour necrosis factor (TNF) therapies, including infliximab, adalimumab and etanercept. However, after an initial 30 months of successful therapy with tocilizumab, her treatment had been complicated by axillary abscesses, resulting in a temporary discontinuation period of 6 months. Following this break, tocilizumab was recommenced at a reduced frequency of 8 mg/kg once every 3 weeks. Approximately 2 months after recommencing tocilizumab changes in her moles were noted. She had a family history of psoriasis affecting her father and brother, and there was no personal or family history of vitiligo. On physical examination, classic halo naevi were seen at the site of every mole on the patient’s body (Figs 1a-c). There were no areas of vitiligo or changes affecting other naturally pigmented areas such as the hair and eyebrows. None of the naevi appeared clinically atypical, and a thorough skin and eye examination was unremarkable. Histological examination of a biopsy taken from one of the halo naevi showed only features of a benign intradermal naevus. Tocilizumab was withheld initially but soon recommenced in order to achieve control of the patient’s arthritis again. Her moles underwent gradual regression, but failed to repigment following a course of narrowband ultraviolet B phototherapy. However, the patient currently
Clinical and Experimental Dermatology (2014) 39, pp717–719
717
Multiple halo naevi associated with tocilizumab treatment K. Kuet and M. Goodfield
(a)
(b)
(c)
Figure 1 Multiple halo naevi at the sites
of pre-existing moles, with evidence of regression of these moles: (a) posterior trunk, (b) right lateral trunk, (c) posterior lower limbs.
remains well on tocilizumab after a follow-up period of > 2 years. IL-6 has a pathological role in various immune inflammatory diseases, including RA, JIA and Crohn’s disease.1 In addition, IL-6 is a key growth-promoting and antiapoptotic inflammatory cytokine in cancer because of its effects on angiogenesis and inhibition of adaptive anti-tumour immunity.2 IL-6 is produced by many cell types, including keratinocytes and fibroblasts, and also acts as a paracrine inhibitor of human melanocyte proliferation and melanogenesis.3 A halo naevus appears as a melanocytic naevus surrounded by an achromic hypopigmented halo (Fig. 2); the naevus then usually disappears. This immune-mediated phenomenon occurs in around 1% of the population, usually in children and adoles-
Figure 2 Focussed image of a halo naevus, demonstrating an
achromic hypopigmented halo around a regressing naevus.
718
Clinical and Experimental Dermatology (2014) 39, pp717–719
cents.4 Histology often demonstrates a lymphohistiocytic infiltrate directed against melanocytes. The association between halo naevi and vitiligo is well established, although the exact pathogenesis remains unclear. Vitiligo and halo naevi may share similar pathways, as indicated by their autoimmune mechanisms involving a cytotoxic T-cell reaction and their immunological reaction against the same melanocytic-specific targets.5 This has been supported by case reports describing the onset of vitiligo simultaneously with or shortly after the occurrence of a halo naevus. Vitiligo is associated with an imbalance of epidermal cytokines involved with melanocyte function. Compared with normal skin, vitiligo skin has lower expression of melanocyte-stimulating cytokines including granulocyte–monocyte colony-stimulating factor, basic fibroblastic growth factor and stem cell factor. In addition, higher levels of paracrine inhibitors of melanocytes, including IL-6 and TNF-a, have also been noted.3 The development of multiple halo naevi can also be associated with an underlying malignant melanoma, although this is rare. There are no previous reports of tocilizumab-induced multiple halo naevi, but similar cases have been described in association with other immune-modifying drugs. Fabre et al.6 reported a case of multiple halo naevi occurring in a patient with ankylosing spondylitis after 6 weeks of infliximab treatment. This was attributed to the local production and activation of type 1 interferon (IFN), leading to regression of melanomas and melanocytic lesions. A similar case was reported in a patient with multiple sclerosis after 3 months of IFN b-1a therapy. IFN b-1a is associated with stimulation of CD8+ lymphocytes, leading to recognition of melanocyte-derived proteins, and this is thought to play a role in vitiligo.7 Finally, a case of multiple halo naevi was reported in a patient after
ª 2014 British Association of Dermatologists
Multiple halo naevi associated with tocilizumab treatment K. Kuet and M. Goodfield
8 weeks of treatment with imatinib for dermatosarcoma protuberans. Imatinib can cause skin depigmentation through inhibition of c-kit tyrosine kinase function in melanocytes and indirect reduction of melanocyte proliferation, leading to subsequent decrease in melanogenic molecule secretion by cutaneous fibroblasts.8 Based on the current knowledge concerning IL-6 and its role in cancer and melanocyte function, we believe this case of multiple halo naevi is related to tocilizumab, although the exact pathomechanism remains unclear. IL-6 has an inhibitory role in adaptive immunity and therefore tocilizumab, an anti-IL-6 drug, may result in subsequent activation of the adaptive immune system. Tocilizumab competitively inhibits IL-6 signalling by binding to IL-6 receptors, resulting in an increase in serum IL-6 levels.1 An alternative pathomechanism may therefore be related to the alteration in the epidermal cytokine profile secondary to tocilizumab. We hypothesize that the increase in serum IL-6 concentration may have a direct local inhibitory effect on melanocytes, with access by tocilizumab being limited due to a differential size difference between tocilizumab and IL-6; tocilizumab has a molecular weight of 148 kDa, whereas IL-6 has a molecular weight of only 21–28 kDa.9,10 To our knowledge, this is the first report to describe the development of multiple halo naevi in association with tocilizumab. Although the 2-month delay in the onset of halo naevi is consistent with previous reports of biotherapy-related halo naevi, it is not clear why this phenomenon occurred only after tocilizumab was restarted after the temporary discontinuation period. It is possible that there may be as yet undetermined patient-specific factors that may provide further explanations for this unusual case. Although multiple halo naevi are a rare phenomenon, this case highlights a possible association between the onset of multiple halo naevi and the use of immune-modifying therapies.
Learning points Multiple halo naevi are a rare phenomenon
but can occur in children and adolescents. Rare cases of multiple halo naevi have been
reported in association with various immunemodifying drugs. Tocilizumab, a humanized monoclonal antibody directed against the IL-6 receptor, is approved for the treatment of RA and JIA.
ª 2014 British Association of Dermatologists
IL-6 is a key cytokine in cancer because of its
effects on angiogenesis promotion and inhibition of adaptive anti-tumour immunity. IL-6 is also a key cytokine in melanocyte function, for which it acts as a paracrine inhibitor of human melanocyte proliferation and melanogenesis. Tocilizumab may lead to the development of halo naevi secondary to activation of the adaptive immune system or because of the direct inhibitory effects of increased serum IL-6 levels on melanocytes and their function.
References 1 Nishimoto N, Terao K, Mima T et al. Mechanisms and pathologic significances in increase in serum interleukin-6 (IL-6) and soluble receptor after administration of an anti-IL-6 receptor antibody, tocilizumab, in patients with rheumatoid arthritis and Castleman disease. Blood 2008; 112: 3959–64. 2 Germano G, Allavena P, Mantovani A. Cytokines as a key component of cancer-related inflammation. Cytokine 2008; 43: 374–9. 3 Moretti S, Spallanzani A, Amato L et al. New insights into the pathogenesis of vitiligo: imbalance of epidermal cytokines at sites of lesions. Pigment Cell Res 2002; 15: 87–92. 4 Geel NV, Speeckaert R, Lambert L et al. Halo naevi with associated vitiligo-like depigmentations: pathogenetic hypothesis. J Eur Acad Dermatol Venereol 2012; 26: 755–61. 5 Zeff RA, Freitag A, Grin CM, Grant-Kels JM. The immune response in halo naevi. Am Acad Dermatol 1997; 37: 620–4. 6 Fabre C, Dereure O. Worsening alopecia areata and de novo occurrence of multiple halo naevi in a patient receiving infliximab. Dermatology 2008; 216: 185–6. 7 Vera-Iglesias E, Garcıa-Arpa M, S anchez-Caminero P. Halo naevi associated with interferon beta-1a therapy. Actas Dermosifiliogr 2012; 103: 75–6. 8 Fava P, Stroppiana E, Savoia P, Bernengo MG. Halo naevi related to treatment with imatinib in a dermatofibrosarcoma protuberans patient. J Eur Acad Dermatol Venereol 2010; 24: 244–5. 9 Toumpanakis D, Vassilakopoulos T. Molecular mechanisms of action of Interleukin-6 (IL-6). Pneumon 2007; 20: 154–67. 10 Mihara M, Ohsugi Y, Kishimoto T. Tocilizumab, a humanized anti-interleukin-6 receptor antibody, for treatment of rheumatoid arthritis. Open Access Rheumatol Res Rev 2011; 3: 19–29.
Clinical and Experimental Dermatology (2014) 39, pp717–719
719
Clinical dermatology • Concise report
Clinical and Experimental Dermatology
Multiple halo naevi associated with tocilizumab K. Kuet and M. Goodfield Department of Dermatology, Chapel Allerton Hospital, Leeds, West Yorkshire, UK doi:10.1111/ced.12385
Summary
Tocilizumab, a humanized monoclonal antibody directed against the interleukin (IL)-6 receptor, is approved for the treatment of rheumatoid arthritis and juvenile idiopathic arthritis (JIA). We describe a case of multiple halo naevi occurring in a patient with a history of JIA treated with tocilizumab. IL-6 is a key cytokine in the setting of cancer through its effects on angiogenesis and inhibition of adaptive antitumour immunity. IL-6 also plays a role in melanocyte function, and increased levels have been noted in vitiligo skin, where it is a paracrine inhibitor of melanocytes. Tocilizumab may therefore lead to the development of halo naevi secondary to subsequent activation of adaptive immunity. Alternatively, as tocilizumab results in increased serum IL-6 levels, the epidermal cytokine profile is altered. Increased levels of IL-6 may therefore have a direct inhibitory effect on melanocytes, where access by tocilizumab may be limited due to differential size difference.
Tocilizumab, a humanized monoclonal antibody against the interleukin-6 (IL-6) receptor, is licensed for the treatment of rheumatoid arthritis (RA) and systemic juvenile idiopathic arthritis (JIA).1 Tocilizumab reduces joint inflammation, thereby preventing longterm damage and producing improvement in quality of life and function. Reported adverse effects include abnormal liver function tests, transient neutropenia, increase in lipids, and infections due to its immunomodulatory effects.
Report A 33-year-old woman presented with an 8-month history of gradual hypopigmentation affecting all her longstanding moles, and the appearance of a pale rim surrounding every mole. She had a history of discoid eczema, migraines and seropositive JIA since the age of 4 years. Over the 3 years prior to this presentation, her arthritis had been well controlled with tocilizumab (8 mg/kg once every 2 weeks), having previously Correspondence: Dr Kar Hung Kuet, Department of Dermatology, Royal Hallamshire Hospital, Glossop Road, Sheffield, S10 2JF, UK E-mail: [email protected] Conflict of interest: the authors declare that they have no conflicts of interest. Accepted for publication 4 February 2014
ª 2014 British Association of Dermatologists
failed a number of anti-tumour necrosis factor (TNF) therapies, including infliximab, adalimumab and etanercept. However, after an initial 30 months of successful therapy with tocilizumab, her treatment had been complicated by axillary abscesses, resulting in a temporary discontinuation period of 6 months. Following this break, tocilizumab was recommenced at a reduced frequency of 8 mg/kg once every 3 weeks. Approximately 2 months after recommencing tocilizumab changes in her moles were noted. She had a family history of psoriasis affecting her father and brother, and there was no personal or family history of vitiligo. On physical examination, classic halo naevi were seen at the site of every mole on the patient’s body (Figs 1a-c). There were no areas of vitiligo or changes affecting other naturally pigmented areas such as the hair and eyebrows. None of the naevi appeared clinically atypical, and a thorough skin and eye examination was unremarkable. Histological examination of a biopsy taken from one of the halo naevi showed only features of a benign intradermal naevus. Tocilizumab was withheld initially but soon recommenced in order to achieve control of the patient’s arthritis again. Her moles underwent gradual regression, but failed to repigment following a course of narrowband ultraviolet B phototherapy. However, the patient currently
Clinical and Experimental Dermatology (2014) 39, pp717–719
717
Multiple halo naevi associated with tocilizumab treatment K. Kuet and M. Goodfield
(a)
(b)
(c)
Figure 1 Multiple halo naevi at the sites
of pre-existing moles, with evidence of regression of these moles: (a) posterior trunk, (b) right lateral trunk, (c) posterior lower limbs.
remains well on tocilizumab after a follow-up period of > 2 years. IL-6 has a pathological role in various immune inflammatory diseases, including RA, JIA and Crohn’s disease.1 In addition, IL-6 is a key growth-promoting and antiapoptotic inflammatory cytokine in cancer because of its effects on angiogenesis and inhibition of adaptive anti-tumour immunity.2 IL-6 is produced by many cell types, including keratinocytes and fibroblasts, and also acts as a paracrine inhibitor of human melanocyte proliferation and melanogenesis.3 A halo naevus appears as a melanocytic naevus surrounded by an achromic hypopigmented halo (Fig. 2); the naevus then usually disappears. This immune-mediated phenomenon occurs in around 1% of the population, usually in children and adoles-
Figure 2 Focussed image of a halo naevus, demonstrating an
achromic hypopigmented halo around a regressing naevus.
718
Clinical and Experimental Dermatology (2014) 39, pp717–719
cents.4 Histology often demonstrates a lymphohistiocytic infiltrate directed against melanocytes. The association between halo naevi and vitiligo is well established, although the exact pathogenesis remains unclear. Vitiligo and halo naevi may share similar pathways, as indicated by their autoimmune mechanisms involving a cytotoxic T-cell reaction and their immunological reaction against the same melanocytic-specific targets.5 This has been supported by case reports describing the onset of vitiligo simultaneously with or shortly after the occurrence of a halo naevus. Vitiligo is associated with an imbalance of epidermal cytokines involved with melanocyte function. Compared with normal skin, vitiligo skin has lower expression of melanocyte-stimulating cytokines including granulocyte–monocyte colony-stimulating factor, basic fibroblastic growth factor and stem cell factor. In addition, higher levels of paracrine inhibitors of melanocytes, including IL-6 and TNF-a, have also been noted.3 The development of multiple halo naevi can also be associated with an underlying malignant melanoma, although this is rare. There are no previous reports of tocilizumab-induced multiple halo naevi, but similar cases have been described in association with other immune-modifying drugs. Fabre et al.6 reported a case of multiple halo naevi occurring in a patient with ankylosing spondylitis after 6 weeks of infliximab treatment. This was attributed to the local production and activation of type 1 interferon (IFN), leading to regression of melanomas and melanocytic lesions. A similar case was reported in a patient with multiple sclerosis after 3 months of IFN b-1a therapy. IFN b-1a is associated with stimulation of CD8+ lymphocytes, leading to recognition of melanocyte-derived proteins, and this is thought to play a role in vitiligo.7 Finally, a case of multiple halo naevi was reported in a patient after
ª 2014 British Association of Dermatologists
Multiple halo naevi associated with tocilizumab treatment K. Kuet and M. Goodfield
8 weeks of treatment with imatinib for dermatosarcoma protuberans. Imatinib can cause skin depigmentation through inhibition of c-kit tyrosine kinase function in melanocytes and indirect reduction of melanocyte proliferation, leading to subsequent decrease in melanogenic molecule secretion by cutaneous fibroblasts.8 Based on the current knowledge concerning IL-6 and its role in cancer and melanocyte function, we believe this case of multiple halo naevi is related to tocilizumab, although the exact pathomechanism remains unclear. IL-6 has an inhibitory role in adaptive immunity and therefore tocilizumab, an anti-IL-6 drug, may result in subsequent activation of the adaptive immune system. Tocilizumab competitively inhibits IL-6 signalling by binding to IL-6 receptors, resulting in an increase in serum IL-6 levels.1 An alternative pathomechanism may therefore be related to the alteration in the epidermal cytokine profile secondary to tocilizumab. We hypothesize that the increase in serum IL-6 concentration may have a direct local inhibitory effect on melanocytes, with access by tocilizumab being limited due to a differential size difference between tocilizumab and IL-6; tocilizumab has a molecular weight of 148 kDa, whereas IL-6 has a molecular weight of only 21–28 kDa.9,10 To our knowledge, this is the first report to describe the development of multiple halo naevi in association with tocilizumab. Although the 2-month delay in the onset of halo naevi is consistent with previous reports of biotherapy-related halo naevi, it is not clear why this phenomenon occurred only after tocilizumab was restarted after the temporary discontinuation period. It is possible that there may be as yet undetermined patient-specific factors that may provide further explanations for this unusual case. Although multiple halo naevi are a rare phenomenon, this case highlights a possible association between the onset of multiple halo naevi and the use of immune-modifying therapies.
Learning points Multiple halo naevi are a rare phenomenon
but can occur in children and adolescents. Rare cases of multiple halo naevi have been
reported in association with various immunemodifying drugs. Tocilizumab, a humanized monoclonal antibody directed against the IL-6 receptor, is approved for the treatment of RA and JIA.
ª 2014 British Association of Dermatologists
IL-6 is a key cytokine in cancer because of its
effects on angiogenesis promotion and inhibition of adaptive anti-tumour immunity. IL-6 is also a key cytokine in melanocyte function, for which it acts as a paracrine inhibitor of human melanocyte proliferation and melanogenesis. Tocilizumab may lead to the development of halo naevi secondary to activation of the adaptive immune system or because of the direct inhibitory effects of increased serum IL-6 levels on melanocytes and their function.
References 1 Nishimoto N, Terao K, Mima T et al. Mechanisms and pathologic significances in increase in serum interleukin-6 (IL-6) and soluble receptor after administration of an anti-IL-6 receptor antibody, tocilizumab, in patients with rheumatoid arthritis and Castleman disease. Blood 2008; 112: 3959–64. 2 Germano G, Allavena P, Mantovani A. Cytokines as a key component of cancer-related inflammation. Cytokine 2008; 43: 374–9. 3 Moretti S, Spallanzani A, Amato L et al. New insights into the pathogenesis of vitiligo: imbalance of epidermal cytokines at sites of lesions. Pigment Cell Res 2002; 15: 87–92. 4 Geel NV, Speeckaert R, Lambert L et al. Halo naevi with associated vitiligo-like depigmentations: pathogenetic hypothesis. J Eur Acad Dermatol Venereol 2012; 26: 755–61. 5 Zeff RA, Freitag A, Grin CM, Grant-Kels JM. The immune response in halo naevi. Am Acad Dermatol 1997; 37: 620–4. 6 Fabre C, Dereure O. Worsening alopecia areata and de novo occurrence of multiple halo naevi in a patient receiving infliximab. Dermatology 2008; 216: 185–6. 7 Vera-Iglesias E, Garcıa-Arpa M, S anchez-Caminero P. Halo naevi associated with interferon beta-1a therapy. Actas Dermosifiliogr 2012; 103: 75–6. 8 Fava P, Stroppiana E, Savoia P, Bernengo MG. Halo naevi related to treatment with imatinib in a dermatofibrosarcoma protuberans patient. J Eur Acad Dermatol Venereol 2010; 24: 244–5. 9 Toumpanakis D, Vassilakopoulos T. Molecular mechanisms of action of Interleukin-6 (IL-6). Pneumon 2007; 20: 154–67. 10 Mihara M, Ohsugi Y, Kishimoto T. Tocilizumab, a humanized anti-interleukin-6 receptor antibody, for treatment of rheumatoid arthritis. Open Access Rheumatol Res Rev 2011; 3: 19–29.
Clinical and Experimental Dermatology (2014) 39, pp717–719
719
