G Model BONSOI-3938; No. of Pages 2
ARTICLE IN PRESS Joint Bone Spine xxx (2013) xxx–xxx
Available online at www.sciencedirect.com
Case report
HTLV-1-associated arthropathy treated with anti-TNF-alpha agent Laurent Frenzel a,∗ , Bertrand Moura b , Ambroise Marcais a , Hugo Chapdelaine c , Olivier Hermine a a
Service d’hématologie adulte, centre de référence des mastocytoses, CNRS UMR 8147, institut Imagine, hôpital Necker Enfant Malade, 75015 Paris, France 5, Square du Roule, 75008 Paris, France c Service d’immunologie et allergologie, centre hospitalier universitaire de Montréal, 1560, rue Sherbrooke, H2L 4M1 Montreal, Canada b
a r t i c l e
i n f o
Article history: Accepted 8 October 2013 Available online xxx Keywords: HTLV-1 HTLV-1-associated-arthropathy (HAAP) Anti-TNF-alpha T-cell lymphoma
a b s t r a c t Human T cell leukemia virus type 1 or HTLV-1 infection is a public health problem in endemic regions like Japan, Central America or Africa. Although the majority of HTLV-1 carriers remain asymptomatic throughout their lives, some patients could develop neurological disorder, inflammatory arthropathy also called HTLV-1-associated arthropathy or T-cell malignancy, the adult T-cell leukemia/lymphoma or ATL with a very poor prognosis. Described to be very close to rheumatoid arthritis, HTLV-1-associated arthropathy patients have few or no response to the first line therapy with corticosteroids and disease modifying antirheumatic drugs or DMARDs. The use of anti-TNF-␣ agents in these patients is an interesting alternative but asks the question of risk of developing an adult T-Cell leukemia/lymphoma. We reported an exceptional case of a smoldering ATL patient with an HTLV-1-associated arthropathy, refractory to corticosteroid, DMARDs and rituximab therapy, treated successfully with etanercept, without progression to aggressive ATL after 5 years. © 2013 Société franc¸aise de rhumatologie. Published by Elsevier Masson SAS. All rights reserved.
1. Introduction Human T-cell leukemia virus type I (HTLV-1) was the first discovered human retrovirus. Approximately, 10–20 millions are infected in HTLV-1-endemic regions, such as southern Japan, Central and South America, Caribbean, intertropical Africa, northern Iran and Romania [1]. Transmission of HTLV-I occurs from mother to child through breast milk, by sexual contact and exposure to contaminated blood. HTLV-1 is associated with three different clinical subgroups: adult T-cell leukemia (ATL), HTLV-1-associated myelopathy/tropical spastic paraparesis and HTLV-1 uveitis/HTLV1-associated uveitis. In the two last subgroups, several immune disorders are frequently described and putatively linked to HTLV1, such as polymyositis, Sjögren’s syndrome and arthropathy [2]. HTLV-1-associated arthropathy (HAAP) was described to be an entity very close to rheumatoid arthritis (RA) [3,4]. In fact, HAAP shows synovial proliferation with T-cell infiltration. Analyses of synovial tissues from HAAP patients confirm that not only T-cells but also synoviocytes are infected by HTLV-1 and overexpress the viral transactivator protein Tax. Tax induce cell proliferation and proinflammatory cytokine secretion, especially TNF-alpha [5,6]. However, use of TNF-alpha inhibitors in patients carrying HTLV-1 brings the question about the risk of developing ATL. The majority of HTLV-1 carriers remain asymptomatic; lifetime risk of
∗ Corresponding author. Tel.: +33 6 95 20 94 04; fax: +33 1 44 49 52 80. E-mail address: [email protected] (L. Frenzel).
developing ATL is estimated to be up to 5% of infected people. The ATL is an aggressive lymphoid proliferation; HTLV-I causes transformation and clonal expansion of T cells. The diversity in clinical features and prognosis of patients with ATL has led to its subclassification into the following four subtypes: smoldering, chronic and acute leukemic forms and ATL lymphoma. Patient with smoldering and chronic ATL have a median survival of 5 years; those with an acute ATL doesn’t exceed one year [7]. There are no clear determinants that separate those who develop ATL from those who do not develop except HTVL-1 proviral load, which could be an effective marker of evolution towards lymphoma [8]. We reported here an exceptional case of HAAP patient with a smoldering ATL treated successfully with an anti-TNF-alpha agent without progression to aggressive ATL after a 5-year follow-up. 2. Case report A 47-year-old Caribbean woman with an anterior diagnosis of HTLV-1 infection complicated by concurrent smoldering ATL and HAAP was admitted in 2007 for a major flare of polyarthritis. Smoldering ATL was diagnosed in 2002 by the presence of 2% of abnormal peripheral blood lymphocytes CD3+, CD4+, CD7−, CD8− CD25+, DR+ with T cell clonality and specific skin infiltration. Whole body CT scan was completely normal. Family history was positive for fatal aggressive ATL in her mother. Watchful waiting was pursued. The patient had developed polyarthritis few years before the smoldering ATL diagnosis, affecting mainly the hands and particularly wrists, proximal and distal interphalangeal
1297-319X/$ – see front matter © 2013 Société franc¸aise de rhumatologie. Published by Elsevier Masson SAS. All rights reserved. doi:10.1016/j.jbspin.2013.10.006
Please cite this article in press as: Frenzel L, et al. HTLV-1-associated arthropathy treated with anti-TNF-alpha agent. Joint Bone Spine (2013), doi:10.1016/j.jbspin.2013.10.006
G Model BONSOI-3938; No. of Pages 2
ARTICLE IN PRESS L. Frenzel et al. / Joint Bone Spine xxx (2013) xxx–xxx
2
Fig. 1. Standard radiographs of hands. Symmetrical erosion and joints spaces narrowing of carpal bones with ulnar translocation. Multiple symmetrical erosive lesions of 2nd, 3th, 4th, 5th proximal and distal interphalangeal joints with joint space narrowing.
joints (DIP). Blood samples found an elevated C-reactive protein level. Also, antinuclear antibodies and rheumatoid factors were slightly elevated and plains radiographs showed multiples erosions lesions of proximal and distal interphalangeal joints (Fig. 1). Corticosteroids and hydroxychloroquine were poorly effective. Methotrexate was quickly proposed, but unsuccessful in controlling her symptoms. A rituximab-based therapy was performed with four weekly infusions of 375 mg/m2 rituximab, followed by one infusion every 2 months with a very good initial response. No increase of abnormal peripheral lymphocyte count was observed and no progression to aggressive ATL occurred. After 18 months of rituximab therapy, we observed a loss of efficacy. Because of major flare, we decided to introduce a TNF-alpha blocker, etanercept 50 mg subcutaneously every week, despite the risk of developing ATL. After a follow-up of 5 years, no relapse of polyarthritis occurred. We also observed an unexpected decrease of abnormal peripheral lymphocyte count from 2 to 0,1% of total lymphocytes with a loss of T cell clonality. HTLV-1 proviral load was monitored every 6 months; PCR HTLV-1 was stable between 4 and 5 log/106 cells. No progression of the ATL was noticed. 3. Discussion This interesting case leads to discuss two points. First, characteristics of this HAAP are not as close to RA as previously described, specifically in its primary refractoriness to corticosteroids and disease modifying antirheumatic drugs and, predominantly, in its clinical and radiological presentation. Indeed, we observed clinical and radiological destructive arthritis of DIP, not common in RA.
Symmetric distribution and lack of bone proliferation differentiate this HAAP from psoriatic arthritis. A new entity of unclassified polyarthritis could be found and lead to search HTLV-1 infection in some patients with those findings. Otherwise, the very good response to anti-TNF-alpha agent after multiple treatment failures asks the question of safety of this drug in HAAP patients. In fact, many reports have mentioned risks of lymphoma in patients treated with anti-TNF-alpha [9,10]. However, although this case of smoldering ATL and HAAP association is unusual, the non-progression of ATL after 5 years of anti-TNFalpha therapy in a very highly risk patient is somewhat reassuring. Anti-TNF-alpha agent could be an effective and safe treatment in patients with HTLV-1 infection, especially in endemic region. Of course, a close monitoring is necessarily to follow those patients. HTLV-1 proviral load and peripheral blood T cell by flow cytometry with T cell clonality must be proposed every 3 to 6 months. Peripheral nodes must be checked every 3 months, possibly supplemented by a CT scan in case of deep lymph nodes. If any biological or clinical surrogate markers of HTLV-1 infection were significantly increased, the anti-TNF-␣ agent must be stopped. This exceptional case of HAAP treated by anti-TNF-␣ must sensitize practitioners to this diagnosis and to realise an HTLV-1 blood test to patients from an endemic area with an atypical arthropathy. Even anti-TNF-␣ treatment seems to be effective, further investigation must be performed to confirm the safe use of anti-TNF agent in HTLV-1 seropositive patients. Disclosure of interest The authors declare that they have no conflicts of interest concerning this article. References [1] Kaplan JE, Khabbaz RF. The epidemiology of human T-lymphotropic virus types I and II. Med Virol 1993;3:137–48. [2] Hui Y, Futoshi H, Ichiro Y, et al. Pulmonary complications in human T-cell lymphotropic virus type 1 carriers with Sjögren’s syndrome, three case reports. Rheumatol Int 2009;30:253–8. [3] Hasunuma T, Sumida T, Nishioka K. Human T cell leukemia virus type-I and rheumatoid arthritis. Int Rev Immunol 1998;17:291–307. [4] Kiyoshi H, Junko NY, Masahide A, et al. The human T cell leukemia virus type I-tax gene is responsible for the development of both inflammatory polyarthropathy resembling rheumatoid arthritis and non inflammatory ankylotic arthropathy in transgenic mice. J Immunol 1999;162:2956–63. [5] Kitajima I, Yamamoto K, Sato K, et al. Detection of human T cell lymphotropic virus type I proviral DNA and its gene expression in synovial cells in chronic inflammatory arthropathy. J Clin Invest 1991;88:1315–22. [6] Yin W, Hasunuma T, Kobata T, et al. Synovial hyperplasia in HTLV-1 associated arthropathy is induced by tumor necrosis factor-alpha produced by HTLV-1 infected CD68+ cells. J Rheumatol 2000;27:874–81. [7] Bazarbachi A, Suarez F, Fields P, et al. How I treat adult T-cell leukemia/lymphoma. Blood 2011;118:1736–45. [8] Iwanaga M, Watanabe T, Utsunomiya A, et al. Human T-cell leukemia virus type I (HTLV-1) proviral load and disease progression in asymptomatic HTLV-1 carriers: a nationwide prospective study in Japan. Blood 2010;119:1211–9. [9] Mariette X, Tubach F, Bagheri H, et al. Lymphoma in patients treated with antiTNF: results of the 3-year prospective French RATIO registry. Ann Rheum Dis 2010;69:400–8. [10] Brown SL, Greene MH, Gershon SK, et al. Tumor necrosis factor antagonist therapy and lymphoma development: twenty-six cases reported to the Food and Drug Administration. Arthritis Rheum 2002;46:3151–8.
Please cite this article in press as: Frenzel L, et al. HTLV-1-associated arthropathy treated with anti-TNF-alpha agent. Joint Bone Spine (2013), doi:10.1016/j.jbspin.2013.10.006
ARTICLE IN PRESS Joint Bone Spine xxx (2013) xxx–xxx
Available online at www.sciencedirect.com
Case report
HTLV-1-associated arthropathy treated with anti-TNF-alpha agent Laurent Frenzel a,∗ , Bertrand Moura b , Ambroise Marcais a , Hugo Chapdelaine c , Olivier Hermine a a
Service d’hématologie adulte, centre de référence des mastocytoses, CNRS UMR 8147, institut Imagine, hôpital Necker Enfant Malade, 75015 Paris, France 5, Square du Roule, 75008 Paris, France c Service d’immunologie et allergologie, centre hospitalier universitaire de Montréal, 1560, rue Sherbrooke, H2L 4M1 Montreal, Canada b
a r t i c l e
i n f o
Article history: Accepted 8 October 2013 Available online xxx Keywords: HTLV-1 HTLV-1-associated-arthropathy (HAAP) Anti-TNF-alpha T-cell lymphoma
a b s t r a c t Human T cell leukemia virus type 1 or HTLV-1 infection is a public health problem in endemic regions like Japan, Central America or Africa. Although the majority of HTLV-1 carriers remain asymptomatic throughout their lives, some patients could develop neurological disorder, inflammatory arthropathy also called HTLV-1-associated arthropathy or T-cell malignancy, the adult T-cell leukemia/lymphoma or ATL with a very poor prognosis. Described to be very close to rheumatoid arthritis, HTLV-1-associated arthropathy patients have few or no response to the first line therapy with corticosteroids and disease modifying antirheumatic drugs or DMARDs. The use of anti-TNF-␣ agents in these patients is an interesting alternative but asks the question of risk of developing an adult T-Cell leukemia/lymphoma. We reported an exceptional case of a smoldering ATL patient with an HTLV-1-associated arthropathy, refractory to corticosteroid, DMARDs and rituximab therapy, treated successfully with etanercept, without progression to aggressive ATL after 5 years. © 2013 Société franc¸aise de rhumatologie. Published by Elsevier Masson SAS. All rights reserved.
1. Introduction Human T-cell leukemia virus type I (HTLV-1) was the first discovered human retrovirus. Approximately, 10–20 millions are infected in HTLV-1-endemic regions, such as southern Japan, Central and South America, Caribbean, intertropical Africa, northern Iran and Romania [1]. Transmission of HTLV-I occurs from mother to child through breast milk, by sexual contact and exposure to contaminated blood. HTLV-1 is associated with three different clinical subgroups: adult T-cell leukemia (ATL), HTLV-1-associated myelopathy/tropical spastic paraparesis and HTLV-1 uveitis/HTLV1-associated uveitis. In the two last subgroups, several immune disorders are frequently described and putatively linked to HTLV1, such as polymyositis, Sjögren’s syndrome and arthropathy [2]. HTLV-1-associated arthropathy (HAAP) was described to be an entity very close to rheumatoid arthritis (RA) [3,4]. In fact, HAAP shows synovial proliferation with T-cell infiltration. Analyses of synovial tissues from HAAP patients confirm that not only T-cells but also synoviocytes are infected by HTLV-1 and overexpress the viral transactivator protein Tax. Tax induce cell proliferation and proinflammatory cytokine secretion, especially TNF-alpha [5,6]. However, use of TNF-alpha inhibitors in patients carrying HTLV-1 brings the question about the risk of developing ATL. The majority of HTLV-1 carriers remain asymptomatic; lifetime risk of
∗ Corresponding author. Tel.: +33 6 95 20 94 04; fax: +33 1 44 49 52 80. E-mail address: [email protected] (L. Frenzel).
developing ATL is estimated to be up to 5% of infected people. The ATL is an aggressive lymphoid proliferation; HTLV-I causes transformation and clonal expansion of T cells. The diversity in clinical features and prognosis of patients with ATL has led to its subclassification into the following four subtypes: smoldering, chronic and acute leukemic forms and ATL lymphoma. Patient with smoldering and chronic ATL have a median survival of 5 years; those with an acute ATL doesn’t exceed one year [7]. There are no clear determinants that separate those who develop ATL from those who do not develop except HTVL-1 proviral load, which could be an effective marker of evolution towards lymphoma [8]. We reported here an exceptional case of HAAP patient with a smoldering ATL treated successfully with an anti-TNF-alpha agent without progression to aggressive ATL after a 5-year follow-up. 2. Case report A 47-year-old Caribbean woman with an anterior diagnosis of HTLV-1 infection complicated by concurrent smoldering ATL and HAAP was admitted in 2007 for a major flare of polyarthritis. Smoldering ATL was diagnosed in 2002 by the presence of 2% of abnormal peripheral blood lymphocytes CD3+, CD4+, CD7−, CD8− CD25+, DR+ with T cell clonality and specific skin infiltration. Whole body CT scan was completely normal. Family history was positive for fatal aggressive ATL in her mother. Watchful waiting was pursued. The patient had developed polyarthritis few years before the smoldering ATL diagnosis, affecting mainly the hands and particularly wrists, proximal and distal interphalangeal
1297-319X/$ – see front matter © 2013 Société franc¸aise de rhumatologie. Published by Elsevier Masson SAS. All rights reserved. doi:10.1016/j.jbspin.2013.10.006
Please cite this article in press as: Frenzel L, et al. HTLV-1-associated arthropathy treated with anti-TNF-alpha agent. Joint Bone Spine (2013), doi:10.1016/j.jbspin.2013.10.006
G Model BONSOI-3938; No. of Pages 2
ARTICLE IN PRESS L. Frenzel et al. / Joint Bone Spine xxx (2013) xxx–xxx
2
Fig. 1. Standard radiographs of hands. Symmetrical erosion and joints spaces narrowing of carpal bones with ulnar translocation. Multiple symmetrical erosive lesions of 2nd, 3th, 4th, 5th proximal and distal interphalangeal joints with joint space narrowing.
joints (DIP). Blood samples found an elevated C-reactive protein level. Also, antinuclear antibodies and rheumatoid factors were slightly elevated and plains radiographs showed multiples erosions lesions of proximal and distal interphalangeal joints (Fig. 1). Corticosteroids and hydroxychloroquine were poorly effective. Methotrexate was quickly proposed, but unsuccessful in controlling her symptoms. A rituximab-based therapy was performed with four weekly infusions of 375 mg/m2 rituximab, followed by one infusion every 2 months with a very good initial response. No increase of abnormal peripheral lymphocyte count was observed and no progression to aggressive ATL occurred. After 18 months of rituximab therapy, we observed a loss of efficacy. Because of major flare, we decided to introduce a TNF-alpha blocker, etanercept 50 mg subcutaneously every week, despite the risk of developing ATL. After a follow-up of 5 years, no relapse of polyarthritis occurred. We also observed an unexpected decrease of abnormal peripheral lymphocyte count from 2 to 0,1% of total lymphocytes with a loss of T cell clonality. HTLV-1 proviral load was monitored every 6 months; PCR HTLV-1 was stable between 4 and 5 log/106 cells. No progression of the ATL was noticed. 3. Discussion This interesting case leads to discuss two points. First, characteristics of this HAAP are not as close to RA as previously described, specifically in its primary refractoriness to corticosteroids and disease modifying antirheumatic drugs and, predominantly, in its clinical and radiological presentation. Indeed, we observed clinical and radiological destructive arthritis of DIP, not common in RA.
Symmetric distribution and lack of bone proliferation differentiate this HAAP from psoriatic arthritis. A new entity of unclassified polyarthritis could be found and lead to search HTLV-1 infection in some patients with those findings. Otherwise, the very good response to anti-TNF-alpha agent after multiple treatment failures asks the question of safety of this drug in HAAP patients. In fact, many reports have mentioned risks of lymphoma in patients treated with anti-TNF-alpha [9,10]. However, although this case of smoldering ATL and HAAP association is unusual, the non-progression of ATL after 5 years of anti-TNFalpha therapy in a very highly risk patient is somewhat reassuring. Anti-TNF-alpha agent could be an effective and safe treatment in patients with HTLV-1 infection, especially in endemic region. Of course, a close monitoring is necessarily to follow those patients. HTLV-1 proviral load and peripheral blood T cell by flow cytometry with T cell clonality must be proposed every 3 to 6 months. Peripheral nodes must be checked every 3 months, possibly supplemented by a CT scan in case of deep lymph nodes. If any biological or clinical surrogate markers of HTLV-1 infection were significantly increased, the anti-TNF-␣ agent must be stopped. This exceptional case of HAAP treated by anti-TNF-␣ must sensitize practitioners to this diagnosis and to realise an HTLV-1 blood test to patients from an endemic area with an atypical arthropathy. Even anti-TNF-␣ treatment seems to be effective, further investigation must be performed to confirm the safe use of anti-TNF agent in HTLV-1 seropositive patients. Disclosure of interest The authors declare that they have no conflicts of interest concerning this article. References [1] Kaplan JE, Khabbaz RF. The epidemiology of human T-lymphotropic virus types I and II. Med Virol 1993;3:137–48. [2] Hui Y, Futoshi H, Ichiro Y, et al. Pulmonary complications in human T-cell lymphotropic virus type 1 carriers with Sjögren’s syndrome, three case reports. Rheumatol Int 2009;30:253–8. [3] Hasunuma T, Sumida T, Nishioka K. Human T cell leukemia virus type-I and rheumatoid arthritis. Int Rev Immunol 1998;17:291–307. [4] Kiyoshi H, Junko NY, Masahide A, et al. The human T cell leukemia virus type I-tax gene is responsible for the development of both inflammatory polyarthropathy resembling rheumatoid arthritis and non inflammatory ankylotic arthropathy in transgenic mice. J Immunol 1999;162:2956–63. [5] Kitajima I, Yamamoto K, Sato K, et al. Detection of human T cell lymphotropic virus type I proviral DNA and its gene expression in synovial cells in chronic inflammatory arthropathy. J Clin Invest 1991;88:1315–22. [6] Yin W, Hasunuma T, Kobata T, et al. Synovial hyperplasia in HTLV-1 associated arthropathy is induced by tumor necrosis factor-alpha produced by HTLV-1 infected CD68+ cells. J Rheumatol 2000;27:874–81. [7] Bazarbachi A, Suarez F, Fields P, et al. How I treat adult T-cell leukemia/lymphoma. Blood 2011;118:1736–45. [8] Iwanaga M, Watanabe T, Utsunomiya A, et al. Human T-cell leukemia virus type I (HTLV-1) proviral load and disease progression in asymptomatic HTLV-1 carriers: a nationwide prospective study in Japan. Blood 2010;119:1211–9. [9] Mariette X, Tubach F, Bagheri H, et al. Lymphoma in patients treated with antiTNF: results of the 3-year prospective French RATIO registry. Ann Rheum Dis 2010;69:400–8. [10] Brown SL, Greene MH, Gershon SK, et al. Tumor necrosis factor antagonist therapy and lymphoma development: twenty-six cases reported to the Food and Drug Administration. Arthritis Rheum 2002;46:3151–8.
Please cite this article in press as: Frenzel L, et al. HTLV-1-associated arthropathy treated with anti-TNF-alpha agent. Joint Bone Spine (2013), doi:10.1016/j.jbspin.2013.10.006
