Clin Drug Investig (2014) 34:159–161 DOI 10.1007/s40261-013-0159-9
CASE REPORT
Tocilizumab Monotherapy in a Patient with Rheumatoid Arthritis and Iatrogenic Kaposi Sarcoma Francesca Ingegnoli • Athanasia Tourlaki Roberta Gualtierotti
•
Published online: 5 December 2013 Ó Springer International Publishing Switzerland 2013
Abstract Kaposi sarcoma (KS) is a human herpesvirus8-associated lymphoangioproliferative neoplasm. Both human and viral interleukin-6 (IL-6) proteins seem to drive much of the clinical manifestations of KS, which provides a new target for intervention by using IL-6-neutralizing antibodies. We describe the clinical course of a patient in whom tocilizumab, a monoclonal anti-IL-6 receptor antibody approved for rheumatoid arthritis (RA) treatment, was effective not only in inducing RA remission but was also safe for KS.
proposed as valuable treatment strategy for other systemic inflammatory rheumatic diseases [3]. Iatrogenic Kaposi’s sarcoma (KS) is a variant of the malignant tumor of endothelial and vascular smooth muscle cells, reported in patients treated with immunosuppressive and/or corticosteroid therapy [4]. Here we describe a patient with RA and iatrogenic KS in whom treatment with tocilizumab was not only effective in inducing RA remission but was also safe for KS.
2 Case Report 1 Introduction Tocilizumab, a humanized anti-human interleukin-6 (IL-6) receptor (IL-6R) monoclonal antibody, was developed in Japan as the first biological disease-modifying antirheumatic drug (DMARD) targeting IL-6Rs. It has been approved for the treatment of rheumatoid arthritis (RA). Tocilizumab has been shown to be effective in RA in combination with traditional DMARDs and in monotherapy as its efficacy in reducing signs and symptoms of RA and structural damage is both comparable with combination therapy with methotrexate and superior to adalimumab monotherapy [1, 2]. Recently, it has also been
F. Ingegnoli (&) R. Gualtierotti Division of Rheumatology, Istituto Gaetano Pini, Department of Clinical Sciences and Community Health, University of Milano, Piazza Cardinal Ferrari 1, 20122 Milan, Italy e-mail: [email protected] A. Tourlaki Dermatology Unit, Fondazione IRCCS Ca’ Granda, Ospedale Maggiore Policlinico, Milan, Italy
In 2000, a 41-year-old man had symmetric polyarthritis involving small joints of the hands and feet, knees and ankles, his first symptoms of what proved to be RA. Serologic analysis was positive for rheumatoid factors (60 IU/dL) and anti-citrullinated peptide antibodies (223 IU/dL). He had been treated successfully with corticosteroids (prednisone 7.5 mg/day) and intramuscular injection of methotrexate (15 mg/week) over a period of 11 years. His medical history was also notable for atrial fibrillation in 2005 and deep vein thrombosis in 2010. In June 2011, the patient’s physician observed macular skin lesions affecting the lower limbs during a routine visit. Skin biopsy was consistent with KS positive for human herpesvirus-8 (HHV-8). He tested negative for HIV-1 and -2 antibodies and p24 antigen. Hence, iatrogenic KS was diagnosed, methotrexate and prednisone were discontinued, and involution of KS lesions occurred. After 3 months, the patient’s clinical course was further complicated by severe RA relapse. Sulphasalazine treatment (up to 3 g/day) was initiated but was discontinued because of itchy maculopapular skin rash after 1 month. Parenteral gold salts (50 mg once a week) were also given,
160
but were stopped after 3 months because of severe proteinuria (4.1 g/24 h) that resolved within 3 months after drug discontinuation. Hydroxychloroquine (400 mg/day) was then used for 6 months, but his condition continued to deteriorate. Given the failure of other therapy and the lack of other options, we administered intravenous tocilizumab (8 mg/kg monthly) under strict monitoring of rheumatologists and dermatologists. Before the first tocilizumab infusion, the patient had persistent very active RA [Disease Activity Score (DAS)28: 5.2]. Analysis for hepatitis C and B virus, HHV-8 viremia, and tuberculosis were negative. Anti-HHV-8 antibodies were highly positive; erythrocyte sedimentation rate (ESR) was 38 mm/h; C-reactive protein (CRP) was 8.00 mg/dL (\5 mg/dL); hemoglobin (Hb) was 11.7 mg/dL; IL-6 was 31.49 pg/mL (3.12–12.5 pg/mL), and soluble IL-6R was 65,502 pg/mL (15,000–40,000 pg/mL). Liver function and lipid profile were normal. Shortly after beginning tocilizumab, his condition started to improve, obtaining RA clinical remission in a 6-month period. After six tocilizumab infusions, DAS-28 was 0; ESR and CRP were negative; HHV-8 viremia was still negative; Hb was 14.8 mg/dL; IL-6 was 7.7 pg/mL; IL-6R levels were 182,171 pg/mL; and liver function and lipid profile were still normal. To date, the patient is still experiencing RA and KS remission. Tocilizumab is well-tolerated and without any side effects.
3 Discussion and Conclusion This is the first report of the safe use of tocilizumab in an RA patient with iatrogenic KS. Iatrogenic KS has been previously reported in immunocompromised rheumatic patients receiving prolonged treatment with non-biologic DMARDs [5]; similarly, iatrogenic KS has been described after treatment with anti-tumor necrosis factor-a agents [6– 8], and in these cases the only therapeutic approach was the decrease or discontinuation of treatment. By contrast, rituximab therapy has been considered to be a potential therapeutic option, but was discarded due to the controversial published results [9–12]. We consider tocilizumab to be an attractive therapeutic option because data from basic research demonstrate that high levels of human and viral IL-6 are detectable in association with active HHV-8 replication, and because viral IL-6, as well as human IL-6, seems to drive much of the clinical manifestations of HHV-8-related syndromes [13–16]. This provides a new target for intervention of tocilizumab in malignant and non-malignant HHV-8-related syndromes such as KS. By contrast, since the first
F. Ingegnoli et al.
report in 1994, it has been used successfully in multicentric Castleman’s disease, an HHV-8-related lymphoproliferative disorder [17]. The side effect profile of tocilizumab is largely consistent with regards to liver toxicity and hypercholesterolemia, but these are not associated with clinical symptoms or an excess in major adverse cardiovascular events. Moreover, serious infections (including bacterial, mycobacterial, viral, or other opportunistic infections) have been reported, particularly in patients receiving concomitant therapy with other immunosuppressive agents. In this patient, the potential risks and benefits of the drug prior to initiating therapy have been considered and the patient has been monitored by rheumatologists and dermatologists [1–3]. Since no KS recurrence was observed under tocilizumab monotherapy, this case suggests that tocilizumab may be a feasible therapeutic option in rheumatic patients with iatrogenic KS and could pave the way for new studies of KS treatment. Conflict of interest No funding has been received for this preparation of this case report. The authors state that they have no conflicts of interest.
References 1. Genovese MC, McKay JD, Nasonov EL, et al. Interleukin-6 receptor inhibition with tocilizumab reduces disease activity in rheumatoid arthritis with inadequate response to disease-modifying antirheumatic drugs: the tocilizumab in combination with traditional disease-modifying antirheumatic drug therapy study. Arthritis Rheum. 2008;58(10):2968–80. 2. Dougados M, Kissel K, Sheeran T, et al. Adding tocilizumab or switching to tocilizumab monotherapy in methotrexate inadequate responders: 24-week symptomatic and structural results of a 2-year randomised controlled strategy trial in rheumatoid arthritis (ACT-RAY). Ann Rheum Dis. 2013;72(1):43–50. 3. Alten R, Maleitzke T. Tocilizumab: a novel humanized antiinterleukin 6 (IL-6) receptor antibody for the treatment of patients with non-RA systemic, inflammatory rheumatic diseases. Ann Med. 2013;45(4):357–63. 4. Antman K, Chang Y. Kaposi’s sarcoma. N Engl J Med. 2000;342(14):1027–38. 5. Mezalek ZT, Harmouche H, Attar NE, et al. Kaposi’s sarcoma in association with Behcet’s disease: case report and literature review. Semin Arthritis Rheum. 2007;36(5):328–31. 6. Martı´nez-Martı´nez ML, Pe´rez-Garcı´a LJ, Escario-Travesedo E, et al. Kaposi sarcoma associated with infliximab treatment. Actas Dermosifiliogr. 2010;101(5):462–4. 7. Ursini F, Naty S, Mazzei V, et al. Kaposi’s sarcoma in a psoriatic arthritis patient treated with infliximab. Int Immunopharmacol. 2010;10(7):827–8. 8. Cohen CD, Horster S, Sander CA, et al. Kaposi’s sarcoma associated with tumour necrosis factor alpha neutralising therapy. Ann Rheum Dis. 2003;62(7):684. 9. Law AB, Ryan G, Lade S, et al. Development of Kaposi’s sarcoma after complete remission of multicentric Castlemans
Tocilizumab in Rheumatoid Arthritis with Kaposi Sarcoma
10.
11.
12. 13.
disease with rituximab therapy in a HHV8-positive, HIV-negative patient. Int J Hematol. 2010;91(2):347–8. Nicoli P, Familiari U, Bosa M, et al. HHV8-positive, HIV-negative multicentric Castleman’s disease: early and sustained complete remission with rituximab therapy without reactivation of Kaposi sarcoma. Int J Hematol. 2009;90(3):392–6. Terasaki Y, Okumura H, Saito K, et al. HHV-8/KSHV-negative and CD20-positive primary effusion lymphoma successfully treated by pleural drainage followed by chemotherapy containing rituximab. Intern Med. 2008;47(24):2175–8. Pantanowitz L, Fru¨h K, Marconi S, et al. Pathology of rituximabinduced Kaposi sarcoma flare. BMC Clin Pathol. 2008;23(8):7. Nishimoto N, Terao K, Mima T, et al. Mechanisms and pathologic significances in increase in serum interleukin-6 (IL-6) and soluble IL-6 receptor after administration of an anti-IL-6 receptor antibody, tocilizumab, in patients with rheumatoid arthritis and Castleman disease. Blood. 2008;112(10):3959–64.
161 14. Suthaus J, Stuhlmann-Laeisz C, Tompkins VS, et al. HHV-8encoded viral IL-6 collaborates with mouse IL-6 in the development of multicentric Castleman disease in mice. Blood. 2012;119(22):5173–81. 15. Morris VA, Punjabi AS, Wells RC, et al. The KSHV viral IL-6 homolog is sufficient to induce blood to lymphatic endothelial cell differentiation. Virology. 2012;428(2):112–20. 16. An J, Lichtenstein AK, Brent G, et al. The Kaposi sarcomaassociated herpesvirus (KSHV) induces cellular interleukin 6 expression: role of the KSHV latency-associated nuclear antigen and the AP1 response element. Blood. 2002;99(2):649–54. 17. Beck JT, Hsu SM, Wijdenes J, et al. Alleviation of systemic manifestations of Castleman’s disease by monoclonal anti-interleukin-6 antibody. N Engl J Med. 1994;330(9):602–5.
CASE REPORT
Tocilizumab Monotherapy in a Patient with Rheumatoid Arthritis and Iatrogenic Kaposi Sarcoma Francesca Ingegnoli • Athanasia Tourlaki Roberta Gualtierotti
•
Published online: 5 December 2013 Ó Springer International Publishing Switzerland 2013
Abstract Kaposi sarcoma (KS) is a human herpesvirus8-associated lymphoangioproliferative neoplasm. Both human and viral interleukin-6 (IL-6) proteins seem to drive much of the clinical manifestations of KS, which provides a new target for intervention by using IL-6-neutralizing antibodies. We describe the clinical course of a patient in whom tocilizumab, a monoclonal anti-IL-6 receptor antibody approved for rheumatoid arthritis (RA) treatment, was effective not only in inducing RA remission but was also safe for KS.
proposed as valuable treatment strategy for other systemic inflammatory rheumatic diseases [3]. Iatrogenic Kaposi’s sarcoma (KS) is a variant of the malignant tumor of endothelial and vascular smooth muscle cells, reported in patients treated with immunosuppressive and/or corticosteroid therapy [4]. Here we describe a patient with RA and iatrogenic KS in whom treatment with tocilizumab was not only effective in inducing RA remission but was also safe for KS.
2 Case Report 1 Introduction Tocilizumab, a humanized anti-human interleukin-6 (IL-6) receptor (IL-6R) monoclonal antibody, was developed in Japan as the first biological disease-modifying antirheumatic drug (DMARD) targeting IL-6Rs. It has been approved for the treatment of rheumatoid arthritis (RA). Tocilizumab has been shown to be effective in RA in combination with traditional DMARDs and in monotherapy as its efficacy in reducing signs and symptoms of RA and structural damage is both comparable with combination therapy with methotrexate and superior to adalimumab monotherapy [1, 2]. Recently, it has also been
F. Ingegnoli (&) R. Gualtierotti Division of Rheumatology, Istituto Gaetano Pini, Department of Clinical Sciences and Community Health, University of Milano, Piazza Cardinal Ferrari 1, 20122 Milan, Italy e-mail: [email protected] A. Tourlaki Dermatology Unit, Fondazione IRCCS Ca’ Granda, Ospedale Maggiore Policlinico, Milan, Italy
In 2000, a 41-year-old man had symmetric polyarthritis involving small joints of the hands and feet, knees and ankles, his first symptoms of what proved to be RA. Serologic analysis was positive for rheumatoid factors (60 IU/dL) and anti-citrullinated peptide antibodies (223 IU/dL). He had been treated successfully with corticosteroids (prednisone 7.5 mg/day) and intramuscular injection of methotrexate (15 mg/week) over a period of 11 years. His medical history was also notable for atrial fibrillation in 2005 and deep vein thrombosis in 2010. In June 2011, the patient’s physician observed macular skin lesions affecting the lower limbs during a routine visit. Skin biopsy was consistent with KS positive for human herpesvirus-8 (HHV-8). He tested negative for HIV-1 and -2 antibodies and p24 antigen. Hence, iatrogenic KS was diagnosed, methotrexate and prednisone were discontinued, and involution of KS lesions occurred. After 3 months, the patient’s clinical course was further complicated by severe RA relapse. Sulphasalazine treatment (up to 3 g/day) was initiated but was discontinued because of itchy maculopapular skin rash after 1 month. Parenteral gold salts (50 mg once a week) were also given,
160
but were stopped after 3 months because of severe proteinuria (4.1 g/24 h) that resolved within 3 months after drug discontinuation. Hydroxychloroquine (400 mg/day) was then used for 6 months, but his condition continued to deteriorate. Given the failure of other therapy and the lack of other options, we administered intravenous tocilizumab (8 mg/kg monthly) under strict monitoring of rheumatologists and dermatologists. Before the first tocilizumab infusion, the patient had persistent very active RA [Disease Activity Score (DAS)28: 5.2]. Analysis for hepatitis C and B virus, HHV-8 viremia, and tuberculosis were negative. Anti-HHV-8 antibodies were highly positive; erythrocyte sedimentation rate (ESR) was 38 mm/h; C-reactive protein (CRP) was 8.00 mg/dL (\5 mg/dL); hemoglobin (Hb) was 11.7 mg/dL; IL-6 was 31.49 pg/mL (3.12–12.5 pg/mL), and soluble IL-6R was 65,502 pg/mL (15,000–40,000 pg/mL). Liver function and lipid profile were normal. Shortly after beginning tocilizumab, his condition started to improve, obtaining RA clinical remission in a 6-month period. After six tocilizumab infusions, DAS-28 was 0; ESR and CRP were negative; HHV-8 viremia was still negative; Hb was 14.8 mg/dL; IL-6 was 7.7 pg/mL; IL-6R levels were 182,171 pg/mL; and liver function and lipid profile were still normal. To date, the patient is still experiencing RA and KS remission. Tocilizumab is well-tolerated and without any side effects.
3 Discussion and Conclusion This is the first report of the safe use of tocilizumab in an RA patient with iatrogenic KS. Iatrogenic KS has been previously reported in immunocompromised rheumatic patients receiving prolonged treatment with non-biologic DMARDs [5]; similarly, iatrogenic KS has been described after treatment with anti-tumor necrosis factor-a agents [6– 8], and in these cases the only therapeutic approach was the decrease or discontinuation of treatment. By contrast, rituximab therapy has been considered to be a potential therapeutic option, but was discarded due to the controversial published results [9–12]. We consider tocilizumab to be an attractive therapeutic option because data from basic research demonstrate that high levels of human and viral IL-6 are detectable in association with active HHV-8 replication, and because viral IL-6, as well as human IL-6, seems to drive much of the clinical manifestations of HHV-8-related syndromes [13–16]. This provides a new target for intervention of tocilizumab in malignant and non-malignant HHV-8-related syndromes such as KS. By contrast, since the first
F. Ingegnoli et al.
report in 1994, it has been used successfully in multicentric Castleman’s disease, an HHV-8-related lymphoproliferative disorder [17]. The side effect profile of tocilizumab is largely consistent with regards to liver toxicity and hypercholesterolemia, but these are not associated with clinical symptoms or an excess in major adverse cardiovascular events. Moreover, serious infections (including bacterial, mycobacterial, viral, or other opportunistic infections) have been reported, particularly in patients receiving concomitant therapy with other immunosuppressive agents. In this patient, the potential risks and benefits of the drug prior to initiating therapy have been considered and the patient has been monitored by rheumatologists and dermatologists [1–3]. Since no KS recurrence was observed under tocilizumab monotherapy, this case suggests that tocilizumab may be a feasible therapeutic option in rheumatic patients with iatrogenic KS and could pave the way for new studies of KS treatment. Conflict of interest No funding has been received for this preparation of this case report. The authors state that they have no conflicts of interest.
References 1. Genovese MC, McKay JD, Nasonov EL, et al. Interleukin-6 receptor inhibition with tocilizumab reduces disease activity in rheumatoid arthritis with inadequate response to disease-modifying antirheumatic drugs: the tocilizumab in combination with traditional disease-modifying antirheumatic drug therapy study. Arthritis Rheum. 2008;58(10):2968–80. 2. Dougados M, Kissel K, Sheeran T, et al. Adding tocilizumab or switching to tocilizumab monotherapy in methotrexate inadequate responders: 24-week symptomatic and structural results of a 2-year randomised controlled strategy trial in rheumatoid arthritis (ACT-RAY). Ann Rheum Dis. 2013;72(1):43–50. 3. Alten R, Maleitzke T. Tocilizumab: a novel humanized antiinterleukin 6 (IL-6) receptor antibody for the treatment of patients with non-RA systemic, inflammatory rheumatic diseases. Ann Med. 2013;45(4):357–63. 4. Antman K, Chang Y. Kaposi’s sarcoma. N Engl J Med. 2000;342(14):1027–38. 5. Mezalek ZT, Harmouche H, Attar NE, et al. Kaposi’s sarcoma in association with Behcet’s disease: case report and literature review. Semin Arthritis Rheum. 2007;36(5):328–31. 6. Martı´nez-Martı´nez ML, Pe´rez-Garcı´a LJ, Escario-Travesedo E, et al. Kaposi sarcoma associated with infliximab treatment. Actas Dermosifiliogr. 2010;101(5):462–4. 7. Ursini F, Naty S, Mazzei V, et al. Kaposi’s sarcoma in a psoriatic arthritis patient treated with infliximab. Int Immunopharmacol. 2010;10(7):827–8. 8. Cohen CD, Horster S, Sander CA, et al. Kaposi’s sarcoma associated with tumour necrosis factor alpha neutralising therapy. Ann Rheum Dis. 2003;62(7):684. 9. Law AB, Ryan G, Lade S, et al. Development of Kaposi’s sarcoma after complete remission of multicentric Castlemans
Tocilizumab in Rheumatoid Arthritis with Kaposi Sarcoma
10.
11.
12. 13.
disease with rituximab therapy in a HHV8-positive, HIV-negative patient. Int J Hematol. 2010;91(2):347–8. Nicoli P, Familiari U, Bosa M, et al. HHV8-positive, HIV-negative multicentric Castleman’s disease: early and sustained complete remission with rituximab therapy without reactivation of Kaposi sarcoma. Int J Hematol. 2009;90(3):392–6. Terasaki Y, Okumura H, Saito K, et al. HHV-8/KSHV-negative and CD20-positive primary effusion lymphoma successfully treated by pleural drainage followed by chemotherapy containing rituximab. Intern Med. 2008;47(24):2175–8. Pantanowitz L, Fru¨h K, Marconi S, et al. Pathology of rituximabinduced Kaposi sarcoma flare. BMC Clin Pathol. 2008;23(8):7. Nishimoto N, Terao K, Mima T, et al. Mechanisms and pathologic significances in increase in serum interleukin-6 (IL-6) and soluble IL-6 receptor after administration of an anti-IL-6 receptor antibody, tocilizumab, in patients with rheumatoid arthritis and Castleman disease. Blood. 2008;112(10):3959–64.
161 14. Suthaus J, Stuhlmann-Laeisz C, Tompkins VS, et al. HHV-8encoded viral IL-6 collaborates with mouse IL-6 in the development of multicentric Castleman disease in mice. Blood. 2012;119(22):5173–81. 15. Morris VA, Punjabi AS, Wells RC, et al. The KSHV viral IL-6 homolog is sufficient to induce blood to lymphatic endothelial cell differentiation. Virology. 2012;428(2):112–20. 16. An J, Lichtenstein AK, Brent G, et al. The Kaposi sarcomaassociated herpesvirus (KSHV) induces cellular interleukin 6 expression: role of the KSHV latency-associated nuclear antigen and the AP1 response element. Blood. 2002;99(2):649–54. 17. Beck JT, Hsu SM, Wijdenes J, et al. Alleviation of systemic manifestations of Castleman’s disease by monoclonal anti-interleukin-6 antibody. N Engl J Med. 1994;330(9):602–5.
