Clin Drug Investig (2014) 34:437–438 DOI 10.1007/s40261-014-0200-7
LETTER TO THE EDITOR
Is Tocilizumab Safe in Kaposi Sarcoma? A Complex Association Among Rheumatoid Arthritis, Psoriasis, and Kaposi Sarcoma Alice Verdelli • Diletta Bonciani • Veronica Bonciolini • Marzia Caproni
Published online: 9 May 2014 Ó Springer International Publishing Switzerland 2014
We read with great interest the recent article by Ingegnoli et al. [1] about a 41-year-old man with a long history of rheumatoid arthritis (RA) who developed iatrogenic Kaposi sarcoma (KS) during immunosuppressive therapy, which resolved after discontinuation of the drugs. Due to RA relapse, tocilizumab was added and led to a clinical remission. The authors suggested that tocilizumab could be safely used even in patients with KS, since no relapse of the neoplasm developed during tocilizumab treatment. They also suggested the possible role of tocilizumab in the treatment of human herpesvirus (HHV)-8-related syndromes such as KS itself. This monoclonal anti-interleukin (IL)-6 receptor antibody is able to block viral IL-6 (vIL-6), an HHV-8-associated herpes virus cytokine homolog, which has a role in neoplasm pathogenesis in association with human IL-6 (hIL-6). Although the hypothesis of Ingegnoli et al. is interesting, our experience did not confirm their results. A 78-year-old woman with a 35-year history of RA not responding to several disease-modifying antirheumatic drugs or tumor necrosis factor-a blockers started tocilizumab monotherapy (8 mg/kg intravenous every 4 weeks). After 13 months of infusion, multiple erythematous, purpuric nodular lesions developed on the anterior surface of both legs, rapidly extending to the posterior surface (Fig. 1a). Upon clinical examination, erythematous-squamous plaques were also observed on the trunk, arms, and neck (Fig. 1b). A skin biopsy of a nodular lesion showed a dermal proliferation of neoplastic spindled cells arranged in fascicles (Fig. 1c).
A. Verdelli (&) D. Bonciani V. Bonciolini M. Caproni Department of Surgery and Translational Medicine, Section of Dermatology, University of Florence, Viale Michelangiolo, 41, 50125 Florence, Italy e-mail: [email protected]
Tumor cells demonstrated nuclear immunoreactivity for HHV-8 (Fig. 1d). By contrast, the skin biopsy of an erythematous-squamous plaque revealed a psoriasiform dermatitis. An iatrogenic KS associated with psoriasis was diagnosed. In accordance with the rheumatologist, tocilizumab was discontinued while gemcitabine, together with topical treatment for psoriasis, was added. After 3 months of gemcitabine treatment, the KS lesions had improved, while the psoriasis had resolved in 3 weeks with topical corticosteroids and vitamin D analogs. In the literature, induction or exacerbation of psoriasis during tocilizumab treatment has been reported with a resolution of skin lesions after discontinuation of the drug, as in our case [2–4]. The nodular lesions were consistent with a diagnosis of iatrogenic KS [5]. To our knowledge, this is the first case of KS developed during tocilizumab treatment. Due to the long period of immunosuppressive therapy received by our patient, it is difficult to establish which drug is implicated in triggering the KS. In contrast to Ingegnoli et al., tocilizumab was found to promote the spread of KS, in addition to previous immunosuppressive drugs or, at the very least, not to be able to treat the disease. hIL-6 and vIL-6 have been implicated in the pathogenesis of HHV-8-related diseases such as KS, primary effusion lymphoma (PEL), multicentric Castleman’s disease (MCD), and in a newly described MCD-like systemic inflammatory syndrome that has been observed in HIVpositive patients [6–8]. Constitutive expression of vIL-6 has been identified in PEL cells and in the immunoblastic cells within the mantle zone of MCD lymph nodes. By contrast, expression of vIL-6 has been undetectable or restricted to few lytically infected cells in KS lesions and only a proportion of KS patients had detectable circulating
438
A. Verdelli et al.
Fig. 1 a Multiple erythematous, purpuric nodular lesions of the legs. b Erythematous-squamous plaques of the trunk. c Skin biopsy specimen: dermal proliferation of neoplastic spindled cells arranged in fascicles (hematoxylin-eosin; original magnification 9250). d Human herpesvirus-8 immunohistochemistry (original magnification 9250)
vIL-6 levels, while an over-expression of hIL-6 is often detectable in KS tissues [9]. In the literature, there is evidence supporting the potential utility of vIL-6 neutralization, at least in the context of MCD and perhaps PEL, but none concerning KS. Differences in IL-6 expression could explain the unsuccessful use of tocilizumab in our patient. Due to the complexity of KS pathogenesis, we suggest the need for further studies to evaluate the role of IL-6 in KS and to evaluate the efficacy and safety of tocilizumab in KS treatment. Acknowledgments No sources of funding were used in the preparation of this manuscript. Conflict of interest
The authors declare no conflict of interest.
References 1. Ingegnoli F, Tourlaki A, Gualtierotti R. Tocilizumab monotherapy in a patient with rheumatoid arthritis and iatrogenic Kaposi sarcoma. Clin Drug Investig. 2014;34:159–61.
2. Grasland A, Mahe´ E, Raynaud E, Mahe´ I. Psoriasis onset with tocilizumab. Jt Bone Spine. 2013;80:541–2. 3. Wendling D, Letho-Gyselinck H, Guillot X, Prati C. Psoriasis onset with tocilizumab treatment for rheumatoid arthritis. J Rheumatol. 2012;39:657. 4. Laurent S, Le Parc JM, Cle´rici T, Bre´ban M, Mahe´ E. Onset of psoriasis following treatment with tocilizumab. Br J Dermatol. 2010;163:1364–5. 5. Dittmer DP, Damania B. Kaposi sarcoma associated herpesvirus pathogenesis (KSHV)—an update. Curr Opin Virol. 2013;3: 238–44. 6. Polizzotto MN, Uldrick TS, Wang V, Aleman K, Wyvill KM, Marshall V, Pittaluga S, O’Mahony D, Whitby D, Tosato G, Steinberg SM, Little RF, Yarchoan R. Human and viral interleukin-6 and other cytokines in Kaposi sarcoma herpesvirus-associated multicentric Castleman disease. Blood. 2013;122:4189–98. 7. Sakakibara S, Tosato G. Viral interleukin-6: role in Kaposi’s sarcoma-associated herpesvirus: associated malignancies. J Interferon Cytokine Res. 2011;31:791–801. 8. Polizzotto MN, Uldrick TS, Hu D, Yarchoan R. Clinical manifestations of Kaposi sarcoma herpesvirus lytic activation: multicentric Castleman disease (KSHV-MCD) and the KSHV inflammatory cytokine syndrome. Front Microbiol. 2012;3:73. 9. Aoki Y, Yarchoan R, Wyvill K, Okamoto S, Little RF, Tosato G. Detection of viral interleukin-6 in Kaposi sarcoma-associated herpesvirus-linked disorders. Blood. 2001;97:2173–6.
LETTER TO THE EDITOR
Is Tocilizumab Safe in Kaposi Sarcoma? A Complex Association Among Rheumatoid Arthritis, Psoriasis, and Kaposi Sarcoma Alice Verdelli • Diletta Bonciani • Veronica Bonciolini • Marzia Caproni
Published online: 9 May 2014 Ó Springer International Publishing Switzerland 2014
We read with great interest the recent article by Ingegnoli et al. [1] about a 41-year-old man with a long history of rheumatoid arthritis (RA) who developed iatrogenic Kaposi sarcoma (KS) during immunosuppressive therapy, which resolved after discontinuation of the drugs. Due to RA relapse, tocilizumab was added and led to a clinical remission. The authors suggested that tocilizumab could be safely used even in patients with KS, since no relapse of the neoplasm developed during tocilizumab treatment. They also suggested the possible role of tocilizumab in the treatment of human herpesvirus (HHV)-8-related syndromes such as KS itself. This monoclonal anti-interleukin (IL)-6 receptor antibody is able to block viral IL-6 (vIL-6), an HHV-8-associated herpes virus cytokine homolog, which has a role in neoplasm pathogenesis in association with human IL-6 (hIL-6). Although the hypothesis of Ingegnoli et al. is interesting, our experience did not confirm their results. A 78-year-old woman with a 35-year history of RA not responding to several disease-modifying antirheumatic drugs or tumor necrosis factor-a blockers started tocilizumab monotherapy (8 mg/kg intravenous every 4 weeks). After 13 months of infusion, multiple erythematous, purpuric nodular lesions developed on the anterior surface of both legs, rapidly extending to the posterior surface (Fig. 1a). Upon clinical examination, erythematous-squamous plaques were also observed on the trunk, arms, and neck (Fig. 1b). A skin biopsy of a nodular lesion showed a dermal proliferation of neoplastic spindled cells arranged in fascicles (Fig. 1c).
A. Verdelli (&) D. Bonciani V. Bonciolini M. Caproni Department of Surgery and Translational Medicine, Section of Dermatology, University of Florence, Viale Michelangiolo, 41, 50125 Florence, Italy e-mail: [email protected]
Tumor cells demonstrated nuclear immunoreactivity for HHV-8 (Fig. 1d). By contrast, the skin biopsy of an erythematous-squamous plaque revealed a psoriasiform dermatitis. An iatrogenic KS associated with psoriasis was diagnosed. In accordance with the rheumatologist, tocilizumab was discontinued while gemcitabine, together with topical treatment for psoriasis, was added. After 3 months of gemcitabine treatment, the KS lesions had improved, while the psoriasis had resolved in 3 weeks with topical corticosteroids and vitamin D analogs. In the literature, induction or exacerbation of psoriasis during tocilizumab treatment has been reported with a resolution of skin lesions after discontinuation of the drug, as in our case [2–4]. The nodular lesions were consistent with a diagnosis of iatrogenic KS [5]. To our knowledge, this is the first case of KS developed during tocilizumab treatment. Due to the long period of immunosuppressive therapy received by our patient, it is difficult to establish which drug is implicated in triggering the KS. In contrast to Ingegnoli et al., tocilizumab was found to promote the spread of KS, in addition to previous immunosuppressive drugs or, at the very least, not to be able to treat the disease. hIL-6 and vIL-6 have been implicated in the pathogenesis of HHV-8-related diseases such as KS, primary effusion lymphoma (PEL), multicentric Castleman’s disease (MCD), and in a newly described MCD-like systemic inflammatory syndrome that has been observed in HIVpositive patients [6–8]. Constitutive expression of vIL-6 has been identified in PEL cells and in the immunoblastic cells within the mantle zone of MCD lymph nodes. By contrast, expression of vIL-6 has been undetectable or restricted to few lytically infected cells in KS lesions and only a proportion of KS patients had detectable circulating
438
A. Verdelli et al.
Fig. 1 a Multiple erythematous, purpuric nodular lesions of the legs. b Erythematous-squamous plaques of the trunk. c Skin biopsy specimen: dermal proliferation of neoplastic spindled cells arranged in fascicles (hematoxylin-eosin; original magnification 9250). d Human herpesvirus-8 immunohistochemistry (original magnification 9250)
vIL-6 levels, while an over-expression of hIL-6 is often detectable in KS tissues [9]. In the literature, there is evidence supporting the potential utility of vIL-6 neutralization, at least in the context of MCD and perhaps PEL, but none concerning KS. Differences in IL-6 expression could explain the unsuccessful use of tocilizumab in our patient. Due to the complexity of KS pathogenesis, we suggest the need for further studies to evaluate the role of IL-6 in KS and to evaluate the efficacy and safety of tocilizumab in KS treatment. Acknowledgments No sources of funding were used in the preparation of this manuscript. Conflict of interest
The authors declare no conflict of interest.
References 1. Ingegnoli F, Tourlaki A, Gualtierotti R. Tocilizumab monotherapy in a patient with rheumatoid arthritis and iatrogenic Kaposi sarcoma. Clin Drug Investig. 2014;34:159–61.
2. Grasland A, Mahe´ E, Raynaud E, Mahe´ I. Psoriasis onset with tocilizumab. Jt Bone Spine. 2013;80:541–2. 3. Wendling D, Letho-Gyselinck H, Guillot X, Prati C. Psoriasis onset with tocilizumab treatment for rheumatoid arthritis. J Rheumatol. 2012;39:657. 4. Laurent S, Le Parc JM, Cle´rici T, Bre´ban M, Mahe´ E. Onset of psoriasis following treatment with tocilizumab. Br J Dermatol. 2010;163:1364–5. 5. Dittmer DP, Damania B. Kaposi sarcoma associated herpesvirus pathogenesis (KSHV)—an update. Curr Opin Virol. 2013;3: 238–44. 6. Polizzotto MN, Uldrick TS, Wang V, Aleman K, Wyvill KM, Marshall V, Pittaluga S, O’Mahony D, Whitby D, Tosato G, Steinberg SM, Little RF, Yarchoan R. Human and viral interleukin-6 and other cytokines in Kaposi sarcoma herpesvirus-associated multicentric Castleman disease. Blood. 2013;122:4189–98. 7. Sakakibara S, Tosato G. Viral interleukin-6: role in Kaposi’s sarcoma-associated herpesvirus: associated malignancies. J Interferon Cytokine Res. 2011;31:791–801. 8. Polizzotto MN, Uldrick TS, Hu D, Yarchoan R. Clinical manifestations of Kaposi sarcoma herpesvirus lytic activation: multicentric Castleman disease (KSHV-MCD) and the KSHV inflammatory cytokine syndrome. Front Microbiol. 2012;3:73. 9. Aoki Y, Yarchoan R, Wyvill K, Okamoto S, Little RF, Tosato G. Detection of viral interleukin-6 in Kaposi sarcoma-associated herpesvirus-linked disorders. Blood. 2001;97:2173–6.
