International Journal of Rheumatic Diseases 2015; 18: 473–475
CORRESPONDENCE
Delights and let-downs in the management of tumor necrosis factor receptor-associated periodic syndrome: the canakinumab experience in a patient with a high-penetrance T50M TNFRSF1A variant Dear Editor, Tumor necrosis factor receptor-associated periodic syndrome (TRAPS) is an autosomal dominant autoinflammatory disorder caused by mutations in the TNFRSF1A gene, encoding the 55-kD receptor type-1 of tumor necrosis factor (TNF)-a.1 This condition is characterized by impaired control of the innate immune system leading to recurrent systemic inflammatory attacks, which consist of fever episodes variously associated with skin involvement, arthromyalgia, conjunctivitis, polyserositis, abdominal or chest pain2 and elevated inflammatory markers.3 Basing on TRAPS pathogenesis, the anti-TNF-a agent etanercept was initially regarded as the cornerstone of treatment.4 However, anti-interleukin (IL)-1 antagonists have recently proven to be effective both in avoiding relapses and in preventing kidney amyloidosis, the most troublesome long-term TRAPS complication.5 Herein we describe a patient carrying a T50M TNFRSF1A mutation, who was treated with the immunoglobulin (Ig)G1 monoclonal antibody against IL-1b canakinumab, but showed loss of efficacy after a 10-month period of complete response. A 36-year-old Caucasian man was admitted to our Unit for a 17-year history of recurrent fevers lasting on average 7 days, spontaneously occurring every other month. In addition to fever, the patient showed myalgia with skin inflammation in the overlying sites, abdominal pain, constipation, arthritis, generalized lymphadenopathy, hepatosplenomegaly and severe fatigue. There was no family history of recurrent fevers. Laboratory investigations revealed highly increased inflammatory markers and mild proteinuria (569 mg/day, normal < 140), while periumbilical adipose tissue biopsy revealed the presence of amyloidosis. Over the last years the patient had been treated with nonsteroidal anti-inflammatory drugs and corticosteroids, reporting only some slight
amelioration. After an inconclusive full diagnostic work-up, the patient’s DNA was analyzed for TNFRSF1A mutations: a heterozygous T50M mutation was found, and final diagnosis of TRAPS established. Treatment with the IL-1 receptor antagonist anakinra (100 mg subcutaneously [s.c.] daily) was started, leading to clinical improvement but also to severely pruritic urticarial lesions. For this reason, canakinumab at the dose of 150 mg s.c. every 4 weeks was started, bringing about complete TRAPS control without any side-effects. Proteinuria regressed. However, after 10 months of full response, three disease relapses occurred with elevation of acute phase reactants and return of slight proteinuria, requiring the restart of high-dose corticosteroids. Among TNFRSF1A mutations, T50M is a high-penetrance variant associated with severe TRAPS phenotype, which has been also related to higher risk of amyloidosis.6 For this reason, since TRAPS treatment is tailored according to the type of mutation as well as to disease activity and eventual complications occurring,7 our patient was treated with anti-IL-1 agents right from the start. Although the anti-IL-1 agents anakinra and canakinumab are emerging as first-line treatment options in this disorder,7 refractoriness to anakinra has been reported in a single patient carrying a T50M mutation.8 In addition, we recently reported one patient carrying a low-penetrance V95M mutation who underwent a partial loss of efficacy toward canakinumab after 18 months: a salvage was first achieved by reducing intervals between canakinumab administrations, and then introducing ‘on-demand’ prednisone.9 In the present case, canakinumab loss of efficacy after a period of 10 months might be linked to several mechanisms, such as immunogenicity deriving from canakinumab, enhanced drug clearance or uncontrolled
© 2014 Asia Pacific League of Associations for Rheumatology and Wiley Publishing Asia Pty Ltd
Correspondence
IL-1 overproduction resulting from imbalance in the cytokine network. Advances in protein engineering technologies and the development of completely new antibodies for established targets, such as humanized or fully human antibodies, has offered advantages in specificity and efficacy. However, these advances only partially address the problem of unwanted immunogenicity, which has become a differentiating factor for biologics in clinical use. In theory, ensuring that the primary sequence of biologic proteins is identical to ‘self’ should reduce the potential for immunogenicity. However, the unexpected development of immune responses to fully human antibodies administered for therapeutic purposes has become one of the greatest puzzles of the protein therapeutics revolution.10 The production of antidrug-antibodies (ADAs) may neutralize the therapeutic effects of the drug and/or alter its pharmacokinetics. Few data are available on the formation of anti-canakinumab antibodies, and unfortunately it was not possible to dose and confirm the presence of anticanakinumab antibodies in our report. In particular, ADAs have been only documented in a few patients and might represent a hypothetical reason to explain partial or complete loss of drug efficacy.11 No clear data are available on the optimal schedule of administration of canakinumab, but the many recent experiences of canakinumab in patients with cryopyrin-associated periodic syndromes has shown that the persistence of a satisfactory control of disease activity requires progressive dose adjustments in more severe patients and that the clinical phenotype represents the main variable determining the need for more frequent administration of the drug at higher dosages.12 Since a concomitant use of immunosuppressive drugs has been useful in reducing the generation of ADAs in patients treated with biotherapies,13 we wonder whether a combination therapy with low-dose immunosuppressive agents could be useful to prevent canakinumab loss of efficacy in patients requiring a life-long therapy. While a concomitant immunosuppressant therapy with the anti-TNF agent infliximab improves outcome of patients with ulcerative colitis and leads to decreased immunogenicity against infliximab,14 evidence for the use of immunosuppressive agents such as methotrexate in autoinflammatory disorders are insufficient. The final outcome of treatment with immunosuppressants should be considered to prolong clinical remission of biologic agents. However, the risk of adverse effects depending upon immunosuppressive agents should be well kept in
474
mind. Data on the efficacy of combination therapy are at this moment insufficient to consider this strategy in patients with autoinflammatory disorders, such as TRAPS, who are resistant to biological therapies.
CONFLICT OF INTEREST Luca Cantarini: Grant/Research support Novartis, SOBI; Consultant: Novartis, SOBI. All other authors have nothing to disclose. Luca CANTARINI1,*, Giuseppe LOPALCO2,*, Antonio VITALE1, Francesco CASO1,3, Giovanni LAPADULA2, Florenzo IANNONE2, Mauro GALEAZZI1 and Donato RIGANTE4 1
Research Center of Systemic Autoimmune and Autoinflammatory Diseases, Policlinico “Le Scotte”, University of Siena, Siena, 2Interdisciplinary Department of Medicine, Rheumatology Unit, Policlinic Hospital, University of Bari, Bari, 3Rheumatology Unit, Department of Medicine DIMED, University of Padua, Padua, and 4 Institute of Pediatrics, Universita Cattolica Sacro Cuore, Rome, Italy *These authors equally contributed to this manuscript. Correspondence: Luca Cantarini, MD, PhD email: [email protected]
REFERENCES 1 McDermott MF, Aksentijevich I, Galon J et al. (1999) Germline mutations in the extracellular domains of the 55 kDa TNF receptor, TNFR1, define a family of dominantly inherited autoinflammatory syndromes. Cell 97, 133–44. 2 Cantarini L, Rigante D, Merlini G et al. (2014) The expanding spectrum of low-penetrance TNFRSF1A gene variants in adults presenting with recurrent inflammatory attacks: clinical manifestations and long-term follow-up. Semin Arthritis Rheum 43, 818–23. 3 Cantarini L, Rigante D, Brizi MG et al. (2012) Clinical and biochemical landmarks in systemic autoinflammatory diseases. Ann Med 44, 664–73. 4 Cantarini L, Rigante D, Lucherini OM et al. (2010) Role of etanercept in the treatment of tumor necrosis factor receptor-associated periodic syndrome: personal experience and review of the literature. Int J Immunopathol Pharmacol 23, 701–7. 5 Obici L, Meini A, Cattalini M et al. (2011) Favourable and sustained response to anakinra in tumour necrosis factor receptor-associated periodic syndrome (TRAPS) with or without AA amyloidosis. Ann Rheum Dis 70, 1511–2.
International Journal of Rheumatic Diseases 2015; 18: 473–475
Correspondence
6 Aksentijevich I, Galon J, Soares M et al. (2001) The tumor-necrosis-factor receptor-associated periodic syndrome: new mutations in TNFRSF1A, ancestral origins, genotype-phenotype studies, and evidence for further genetic heterogeneity of periodic fevers. Am J Hum Genet 69, 301–14. 7 Vitale A, Rigante D, Lucherini OM et al. (2013) Biological treatments: new weapons in the management of monogenic autoinflammatory disorders. Mediators Inflamm 2013, 939847. 8 Quillinan N, Mannion G, Mohammad A et al. (2011) Failure of sustained response to etanercept and refractoriness to anakinra in patients with T50M TNF-receptor-associated periodic syndrome. Ann Rheum Dis 70, 1692–3. 9 Lopalco G, Rigante D, Vitale A, Frediani B, Iannone F, Cantarini L (2014) Tumor necrosis factor receptor-associated periodic syndrome managed with the couple canakinumab-alendronate. Clin Rheumatol [Epub ahead of print]. 10 De Groot AS, Terry F, Cousens L, Martin W (2013) Beyond humanization and de-immunization: tolerization as a
International Journal of Rheumatic Diseases 2015; 18: 473–475
11
12
13
14
method for reducing the immunogenicity of biologics. Expert Rev Clin Pharmacol 6, 651–62. Schlesinger N, Mysler E, Lin HY et al. (2011) Canakinumab reduces the risk of acute gouty arthritis flares during initiation of allopurinol treatment: results of a double-blind, randomised study. Ann Rheum Dis 70, 1264–71. Caorsi R, Lepore L, Zulian F et al. (2013) The schedule of administration of canakinumab in cryopyrin associated periodic syndrome is driven by the phenotype severity rather than the age. Arthritis Res Ther 15, R33. Krieckaert CL, Nurmohamed MT, Wolbink GJ (2012) Methotrexate reduces immunogenicity in adalimumab treated rheumatoid arthritis patients in a dose dependent manner. Ann Rheum Dis 71, 1914–5. Hayes MJ, Stein AC, Sakuraba A (2014) Comparison of efficacy, pharmacokinetics, and immunogenicity between infliximab mono- versus combination therapy in ulcerative colitis. J Gastroenterol Hepatol 29, 1177–85.
475
CORRESPONDENCE
Delights and let-downs in the management of tumor necrosis factor receptor-associated periodic syndrome: the canakinumab experience in a patient with a high-penetrance T50M TNFRSF1A variant Dear Editor, Tumor necrosis factor receptor-associated periodic syndrome (TRAPS) is an autosomal dominant autoinflammatory disorder caused by mutations in the TNFRSF1A gene, encoding the 55-kD receptor type-1 of tumor necrosis factor (TNF)-a.1 This condition is characterized by impaired control of the innate immune system leading to recurrent systemic inflammatory attacks, which consist of fever episodes variously associated with skin involvement, arthromyalgia, conjunctivitis, polyserositis, abdominal or chest pain2 and elevated inflammatory markers.3 Basing on TRAPS pathogenesis, the anti-TNF-a agent etanercept was initially regarded as the cornerstone of treatment.4 However, anti-interleukin (IL)-1 antagonists have recently proven to be effective both in avoiding relapses and in preventing kidney amyloidosis, the most troublesome long-term TRAPS complication.5 Herein we describe a patient carrying a T50M TNFRSF1A mutation, who was treated with the immunoglobulin (Ig)G1 monoclonal antibody against IL-1b canakinumab, but showed loss of efficacy after a 10-month period of complete response. A 36-year-old Caucasian man was admitted to our Unit for a 17-year history of recurrent fevers lasting on average 7 days, spontaneously occurring every other month. In addition to fever, the patient showed myalgia with skin inflammation in the overlying sites, abdominal pain, constipation, arthritis, generalized lymphadenopathy, hepatosplenomegaly and severe fatigue. There was no family history of recurrent fevers. Laboratory investigations revealed highly increased inflammatory markers and mild proteinuria (569 mg/day, normal < 140), while periumbilical adipose tissue biopsy revealed the presence of amyloidosis. Over the last years the patient had been treated with nonsteroidal anti-inflammatory drugs and corticosteroids, reporting only some slight
amelioration. After an inconclusive full diagnostic work-up, the patient’s DNA was analyzed for TNFRSF1A mutations: a heterozygous T50M mutation was found, and final diagnosis of TRAPS established. Treatment with the IL-1 receptor antagonist anakinra (100 mg subcutaneously [s.c.] daily) was started, leading to clinical improvement but also to severely pruritic urticarial lesions. For this reason, canakinumab at the dose of 150 mg s.c. every 4 weeks was started, bringing about complete TRAPS control without any side-effects. Proteinuria regressed. However, after 10 months of full response, three disease relapses occurred with elevation of acute phase reactants and return of slight proteinuria, requiring the restart of high-dose corticosteroids. Among TNFRSF1A mutations, T50M is a high-penetrance variant associated with severe TRAPS phenotype, which has been also related to higher risk of amyloidosis.6 For this reason, since TRAPS treatment is tailored according to the type of mutation as well as to disease activity and eventual complications occurring,7 our patient was treated with anti-IL-1 agents right from the start. Although the anti-IL-1 agents anakinra and canakinumab are emerging as first-line treatment options in this disorder,7 refractoriness to anakinra has been reported in a single patient carrying a T50M mutation.8 In addition, we recently reported one patient carrying a low-penetrance V95M mutation who underwent a partial loss of efficacy toward canakinumab after 18 months: a salvage was first achieved by reducing intervals between canakinumab administrations, and then introducing ‘on-demand’ prednisone.9 In the present case, canakinumab loss of efficacy after a period of 10 months might be linked to several mechanisms, such as immunogenicity deriving from canakinumab, enhanced drug clearance or uncontrolled
© 2014 Asia Pacific League of Associations for Rheumatology and Wiley Publishing Asia Pty Ltd
Correspondence
IL-1 overproduction resulting from imbalance in the cytokine network. Advances in protein engineering technologies and the development of completely new antibodies for established targets, such as humanized or fully human antibodies, has offered advantages in specificity and efficacy. However, these advances only partially address the problem of unwanted immunogenicity, which has become a differentiating factor for biologics in clinical use. In theory, ensuring that the primary sequence of biologic proteins is identical to ‘self’ should reduce the potential for immunogenicity. However, the unexpected development of immune responses to fully human antibodies administered for therapeutic purposes has become one of the greatest puzzles of the protein therapeutics revolution.10 The production of antidrug-antibodies (ADAs) may neutralize the therapeutic effects of the drug and/or alter its pharmacokinetics. Few data are available on the formation of anti-canakinumab antibodies, and unfortunately it was not possible to dose and confirm the presence of anticanakinumab antibodies in our report. In particular, ADAs have been only documented in a few patients and might represent a hypothetical reason to explain partial or complete loss of drug efficacy.11 No clear data are available on the optimal schedule of administration of canakinumab, but the many recent experiences of canakinumab in patients with cryopyrin-associated periodic syndromes has shown that the persistence of a satisfactory control of disease activity requires progressive dose adjustments in more severe patients and that the clinical phenotype represents the main variable determining the need for more frequent administration of the drug at higher dosages.12 Since a concomitant use of immunosuppressive drugs has been useful in reducing the generation of ADAs in patients treated with biotherapies,13 we wonder whether a combination therapy with low-dose immunosuppressive agents could be useful to prevent canakinumab loss of efficacy in patients requiring a life-long therapy. While a concomitant immunosuppressant therapy with the anti-TNF agent infliximab improves outcome of patients with ulcerative colitis and leads to decreased immunogenicity against infliximab,14 evidence for the use of immunosuppressive agents such as methotrexate in autoinflammatory disorders are insufficient. The final outcome of treatment with immunosuppressants should be considered to prolong clinical remission of biologic agents. However, the risk of adverse effects depending upon immunosuppressive agents should be well kept in
474
mind. Data on the efficacy of combination therapy are at this moment insufficient to consider this strategy in patients with autoinflammatory disorders, such as TRAPS, who are resistant to biological therapies.
CONFLICT OF INTEREST Luca Cantarini: Grant/Research support Novartis, SOBI; Consultant: Novartis, SOBI. All other authors have nothing to disclose. Luca CANTARINI1,*, Giuseppe LOPALCO2,*, Antonio VITALE1, Francesco CASO1,3, Giovanni LAPADULA2, Florenzo IANNONE2, Mauro GALEAZZI1 and Donato RIGANTE4 1
Research Center of Systemic Autoimmune and Autoinflammatory Diseases, Policlinico “Le Scotte”, University of Siena, Siena, 2Interdisciplinary Department of Medicine, Rheumatology Unit, Policlinic Hospital, University of Bari, Bari, 3Rheumatology Unit, Department of Medicine DIMED, University of Padua, Padua, and 4 Institute of Pediatrics, Universita Cattolica Sacro Cuore, Rome, Italy *These authors equally contributed to this manuscript. Correspondence: Luca Cantarini, MD, PhD email: [email protected]
REFERENCES 1 McDermott MF, Aksentijevich I, Galon J et al. (1999) Germline mutations in the extracellular domains of the 55 kDa TNF receptor, TNFR1, define a family of dominantly inherited autoinflammatory syndromes. Cell 97, 133–44. 2 Cantarini L, Rigante D, Merlini G et al. (2014) The expanding spectrum of low-penetrance TNFRSF1A gene variants in adults presenting with recurrent inflammatory attacks: clinical manifestations and long-term follow-up. Semin Arthritis Rheum 43, 818–23. 3 Cantarini L, Rigante D, Brizi MG et al. (2012) Clinical and biochemical landmarks in systemic autoinflammatory diseases. Ann Med 44, 664–73. 4 Cantarini L, Rigante D, Lucherini OM et al. (2010) Role of etanercept in the treatment of tumor necrosis factor receptor-associated periodic syndrome: personal experience and review of the literature. Int J Immunopathol Pharmacol 23, 701–7. 5 Obici L, Meini A, Cattalini M et al. (2011) Favourable and sustained response to anakinra in tumour necrosis factor receptor-associated periodic syndrome (TRAPS) with or without AA amyloidosis. Ann Rheum Dis 70, 1511–2.
International Journal of Rheumatic Diseases 2015; 18: 473–475
Correspondence
6 Aksentijevich I, Galon J, Soares M et al. (2001) The tumor-necrosis-factor receptor-associated periodic syndrome: new mutations in TNFRSF1A, ancestral origins, genotype-phenotype studies, and evidence for further genetic heterogeneity of periodic fevers. Am J Hum Genet 69, 301–14. 7 Vitale A, Rigante D, Lucherini OM et al. (2013) Biological treatments: new weapons in the management of monogenic autoinflammatory disorders. Mediators Inflamm 2013, 939847. 8 Quillinan N, Mannion G, Mohammad A et al. (2011) Failure of sustained response to etanercept and refractoriness to anakinra in patients with T50M TNF-receptor-associated periodic syndrome. Ann Rheum Dis 70, 1692–3. 9 Lopalco G, Rigante D, Vitale A, Frediani B, Iannone F, Cantarini L (2014) Tumor necrosis factor receptor-associated periodic syndrome managed with the couple canakinumab-alendronate. Clin Rheumatol [Epub ahead of print]. 10 De Groot AS, Terry F, Cousens L, Martin W (2013) Beyond humanization and de-immunization: tolerization as a
International Journal of Rheumatic Diseases 2015; 18: 473–475
11
12
13
14
method for reducing the immunogenicity of biologics. Expert Rev Clin Pharmacol 6, 651–62. Schlesinger N, Mysler E, Lin HY et al. (2011) Canakinumab reduces the risk of acute gouty arthritis flares during initiation of allopurinol treatment: results of a double-blind, randomised study. Ann Rheum Dis 70, 1264–71. Caorsi R, Lepore L, Zulian F et al. (2013) The schedule of administration of canakinumab in cryopyrin associated periodic syndrome is driven by the phenotype severity rather than the age. Arthritis Res Ther 15, R33. Krieckaert CL, Nurmohamed MT, Wolbink GJ (2012) Methotrexate reduces immunogenicity in adalimumab treated rheumatoid arthritis patients in a dose dependent manner. Ann Rheum Dis 71, 1914–5. Hayes MJ, Stein AC, Sakuraba A (2014) Comparison of efficacy, pharmacokinetics, and immunogenicity between infliximab mono- versus combination therapy in ulcerative colitis. J Gastroenterol Hepatol 29, 1177–85.
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