Clin Rheumatol DOI 10.1007/s10067-014-2556-8
CASE BASED REVIEW
Tumor necrosis factor receptor-associated periodic syndrome managed with the couple canakinumab-alendronate Giuseppe Lopalco & Donato Rigante & Antonio Vitale & Bruno Frediani & Florenzo Iannone & Luca Cantarini
Received: 10 February 2014 / Accepted: 23 February 2014 # Clinical Rheumatology 2014
Abstract Management of tumor necrosis factor receptor-associated periodic syndrome (TRAPS) is puzzling, and therapeutic choices can be complicated, due to both wide genetic heterogeneity and protean clinical phenotype. We report on a 35-year-old female who was diagnosed with TRAPS, after finding the V95M mutation on the TNFRSF1A gene; who was treated in order with etanercept, anakinra, and canakinumab (150 mg/every 8 weeks by subcutaneous injection, then increased to 150 mg every 4 weeks); and who started therapy with oral alendronate (70 mg/weekly) to control her osteoporosis. Alendronate combined with canakinumab led to the optimal clinical control of all TRAPS manifestations and normalization of inflammatory markers. Further studies should be performed to clarify bisphosphonates’ role in the scenery of autoinflammatory disorders.
Keywords Alendronate . Fever . Inflammation . Osteoporosis . Tumor necrosis factor receptor-associated periodic syndrome (TRAPS)
Giuseppe Lopalco and Donato Rigante equally contributed to this manuscript. G. Lopalco : F. Iannone Interdisciplinary Department of Medicine, Rheumatology Unit, Policlinico of Bari, Bari, Italy D. Rigante Institute of Pediatrics, Università Cattolica Sacro Cuore, Rome, Italy A. Vitale : B. Frediani : L. Cantarini (*) Research Center of Systemic Autoimmune and Autoinflammatory Diseases, Rheumatology Unit, Policlinico Le Scotte, University of Siena, Siena, Italy e-mail: [email protected]
Tumor necrosis factor receptor-associated periodic syndrome (TRAPS) is an autosomal dominant autoinflammatory disorder caused by mutations in the TNFRSF1A gene, encoding the tumor necrosis factor (TNF) receptor type 1, which is characterized by subverted innate immune response patterns and recurrent inflammation involving joints, muscles, the skin, serosal membranes, and eyes [1]. We report on a 35-year-old female hospitalized for the first time in May 2009 because of a 2-year history of recurring episodes of high fever (up to 40 °C) lasting 12–15 days, diffuse arthralgia, severe myalgia, and conjunctivitis. Over the past years, she had been long treated with high-dose prednisone (up to 50 mg/day) without reporting any remission. TNFRSF1A genotype revealed the heterozygous V95M mutation: a diagnosis of TRAPS was established. First etanercept (50 mg/week s.c.) and then anakinra (100 mg/ day s.c.) were started with satisfactory results, but she developed painful injection site reactions. Treatment with the human IgG1 anti-interleukin (IL)-1β monoclonal antibody canakinumab (150 mg every 8 weeks s.c.) was started on June 2011, bringing about a prompt resolution of all TRAPS manifestations and normalization of inflammatory markers. However, after 18 months, several disease exacerbations occurred. Subsequently, canakinumab dosage was increased to 150 mg every 4 weeks, obtaining again a rapid control of symptoms, without any side effects. After 6 months of complete clinical remission, chronic low-grade fever and abdominal pain started and persisted, while laboratory investigations showed persistently increased inflammatory markers, thus suggesting a further partial loss of efficacy over time. Meanwhile, because of the previous 2-year corticosteroid administration, the patient’s bone mineral density was evaluated through dual-energy X-ray absorptiometry, and values suggestive of osteoporosis were found (lumbar spine T-score, −2.6; femoral neck T-score, −2.9). For this reason, the patient underwent treatment with oral alendronate (70 mg/week)
Clin Rheumatol
Fig. 1 Erythrocyte sedimentation rate (ESR), serum amyloid-A (SAA), and C-reactive protein (CRP) serum levels during the entire follow-up, pointing-up correlations with treatments, and disease exacerbations. CRP serum levels have been multiplied by 102 in order to allow a better graphical representation; for the same reason, the first ESR and CRP
serum levels have been indicated beside their respective lines rather than shown precisely on the graph. The unit of measure used for y-axis depends on the laboratory data shown (mm/h for ESR, mg/L for SAA, mg/dL × 102 for CRP), while the numbers indicated on x-axis show the months of follow-up since May 2009
along with canakinumab. Unexpectedly, she experienced a clinical amelioration after only 2 days of treatment, and no further inflammatory attacks have occurred over the following 6 months. In addition, the inflammatory parameters erythrosedimentation rate (ESR), serum amyloid-A (SAA), and C-reactive protein (CRP), checked monthly, turned back to normal. Figure 1 shows the ESR, SAA, and CRP before and after alendronate administration. Unfortunately, after 7 months, the onset of gastrointestinal intolerance required alendronate withdrawal at the follow-up visit. Strikingly, despite canakinumab therapy, 7 weeks after alendronate interruption, a further disease relapse with lowgrade fever, abdominal discomfort, and severe myalgia recurred. The patient is currently being treated with canakinumab (150 mg every 4 weeks) and medium-dose prednisone “on demand.” Management of TRAPS is more challenging than in other autoinflammatory syndromes, due to both wide genetic heterogeneity and protean clinical phenotype [2]. At first, etanercept, a recombinant human TNF receptor (p75)-Fc fusion protein, was the mainstay of treatment [3]. IL-1 inhibitors have been shown to induce a longer-lasting effect in controlling TRAPS manifestations and also a more stable normalization of acute-phase reactants [4, 5]. Our surprising result on the overall TRAPS clinical course obtained with oral alendronate, given to control osteoporosis and prevent bone fractures, might be due to the anti-inflammatory properties of nitrogen-containing bisphosphonates, acting on the chronic inflammatory
component of TRAPS itself. In fact, bisphosphonates have revealed anti-inflammatory effects, hindering nitric oxide production in a dose-dependent manner in macrophages [6]. In addition, the induction of apoptosis exerted by different bisphosphonates may have a central role to elucidate their anti-inflammatory effects [7]. On the other hand, bisphosphonates determine a significant depletion in synovial lining macrophages and local reduction of proinflammatory cytokines [8]; in particular, alendronate has been reported to inhibit lipopolysaccharide-induced generation of IL-1β, IL-6, and TNF-α in human monocytes [9]. Since the V95M mutation has been found in patients with a mild TRAPS phenotype [10], a spontaneous disease amelioration cannot be excluded. However, this is not the first case report describing a patient affected with an autoinflammatory disorder responsive to alendronate administration. In fact, a patient affected with mevalonate kinase deficiency (MKD), carrying a homozygous lowpenetrance V377I mutation, has recently shown a complete clinical and laboratory remission soon after alendronate administration. In addition, alendronate discontinuation brought about a typical MKD fever attack, while alendronate resumption during a prolonged fever episode led to the resolution of the attack, strengthening the role of alendronate in this patient [11]. However, in spite of the remarkable results, both this reported TRAPS patient and the one with MVK were suffering from a mild disease variant. It would be interesting to evaluate alendronate treatment also in
Clin Rheumatol
patients carrying high-penetrance mutations, in order to establish if similar beneficial results might be obtained in the presence of severe disease variants with increased disease activity. Notably, our patient showed a partial loss of canakinumab efficacy rather than a complete disease relapse when alendronate was introduced. Certainly, further clinical studies should be performed on a larger number of patients in order to clarify bisphosphonates’ role in the intricate scenery of autoinflammatory disorders. If our results will be confirmed, it will be also interesting to unravel the underlying bisphosphonate mechanism of action. Disclosures Luca Cantarini received grant/research support from Novartis and SOBI and is a consultant for Novartis and SOBI.
References 1. McDermott MF, Aksentijevich I, Galon J, McDermott EM, Ogunkolade BW, Centola M 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 97:133–144 2. Cantarini L, Lucherini OM, Muscari I, Frediani B, Galeazzi M, Brizi MG et al (2012) Tumour necrosis factor receptor-associated periodic
syndrome (TRAPS): state of the art and future perspectives. Autoimmun Rev 12:38–43 3. Cantarini L, Rigante D, Lucherini OM, Cimaz R, Laghi Pasini F, Baldari CT 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 23:701–707 4. Vitale A, Rigante D, Lucherini OM, Caso F, Muscari I, Magnotti F et al (2013) Biological treatments: new weapons in the management of monogenic autoinflammatory disorders. Mediat Inflamm 2013:939847 5. Brizi MG, Galeazzi M, Lucherini OM, Cantarini L, Cimaz R (2012) Successful treatment of tumor necrosis factor receptor-associated periodic syndrome with canakinumab. Ann Intern Med 156:907–908 6. Romas E, Gillespie MT (2006) Inflammation-induced bone loss: can it be prevented? Rheum Dis Clin N Am 32:759–773 7. Bodar EJ, van der Hilst JC, van Heerde W, van der Meer JW, Drenth JP, Simon A (2007) Defective apoptosis of peripheral-blood lymphocytes in hyper-IgD and periodic fever syndrome. Blood 109:2416–2418 8. Cantatore FP, Introsso AM, Carrozzo M (1996) Effects of bisphosphonates on interleukin 1, tumor necrosis factor alpha, and beta 2 microglobulin in rheumatoid arthritis. J Rheumatol 23:1117–1118 9. Sansoni P, Passeri G, Fagnoni F, Mohagheghpour N, Snelli G, Brianti V et al (1995) Inhibition of antigen-presenting cell function by alendronate in vitro. J Bone Miner Res 10:1719–1725 10. Cantarini L, Rigante D, Merlini G, Vitale A, Caso F, Lucherini OM et al (2013) 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. doi:10.1016/j.semarthrit.2013.12.002 11. Cantarini L, Vitale A, Magnotti F, Lucherini OM, Caso F, Frediani B, Galeazzi M, Rigante D (2013) Weekly oral alendronate in mevalonate kinase deficiency. Orphanet J Rare Dis 8:196
CASE BASED REVIEW
Tumor necrosis factor receptor-associated periodic syndrome managed with the couple canakinumab-alendronate Giuseppe Lopalco & Donato Rigante & Antonio Vitale & Bruno Frediani & Florenzo Iannone & Luca Cantarini
Received: 10 February 2014 / Accepted: 23 February 2014 # Clinical Rheumatology 2014
Abstract Management of tumor necrosis factor receptor-associated periodic syndrome (TRAPS) is puzzling, and therapeutic choices can be complicated, due to both wide genetic heterogeneity and protean clinical phenotype. We report on a 35-year-old female who was diagnosed with TRAPS, after finding the V95M mutation on the TNFRSF1A gene; who was treated in order with etanercept, anakinra, and canakinumab (150 mg/every 8 weeks by subcutaneous injection, then increased to 150 mg every 4 weeks); and who started therapy with oral alendronate (70 mg/weekly) to control her osteoporosis. Alendronate combined with canakinumab led to the optimal clinical control of all TRAPS manifestations and normalization of inflammatory markers. Further studies should be performed to clarify bisphosphonates’ role in the scenery of autoinflammatory disorders.
Keywords Alendronate . Fever . Inflammation . Osteoporosis . Tumor necrosis factor receptor-associated periodic syndrome (TRAPS)
Giuseppe Lopalco and Donato Rigante equally contributed to this manuscript. G. Lopalco : F. Iannone Interdisciplinary Department of Medicine, Rheumatology Unit, Policlinico of Bari, Bari, Italy D. Rigante Institute of Pediatrics, Università Cattolica Sacro Cuore, Rome, Italy A. Vitale : B. Frediani : L. Cantarini (*) Research Center of Systemic Autoimmune and Autoinflammatory Diseases, Rheumatology Unit, Policlinico Le Scotte, University of Siena, Siena, Italy e-mail: [email protected]
Tumor necrosis factor receptor-associated periodic syndrome (TRAPS) is an autosomal dominant autoinflammatory disorder caused by mutations in the TNFRSF1A gene, encoding the tumor necrosis factor (TNF) receptor type 1, which is characterized by subverted innate immune response patterns and recurrent inflammation involving joints, muscles, the skin, serosal membranes, and eyes [1]. We report on a 35-year-old female hospitalized for the first time in May 2009 because of a 2-year history of recurring episodes of high fever (up to 40 °C) lasting 12–15 days, diffuse arthralgia, severe myalgia, and conjunctivitis. Over the past years, she had been long treated with high-dose prednisone (up to 50 mg/day) without reporting any remission. TNFRSF1A genotype revealed the heterozygous V95M mutation: a diagnosis of TRAPS was established. First etanercept (50 mg/week s.c.) and then anakinra (100 mg/ day s.c.) were started with satisfactory results, but she developed painful injection site reactions. Treatment with the human IgG1 anti-interleukin (IL)-1β monoclonal antibody canakinumab (150 mg every 8 weeks s.c.) was started on June 2011, bringing about a prompt resolution of all TRAPS manifestations and normalization of inflammatory markers. However, after 18 months, several disease exacerbations occurred. Subsequently, canakinumab dosage was increased to 150 mg every 4 weeks, obtaining again a rapid control of symptoms, without any side effects. After 6 months of complete clinical remission, chronic low-grade fever and abdominal pain started and persisted, while laboratory investigations showed persistently increased inflammatory markers, thus suggesting a further partial loss of efficacy over time. Meanwhile, because of the previous 2-year corticosteroid administration, the patient’s bone mineral density was evaluated through dual-energy X-ray absorptiometry, and values suggestive of osteoporosis were found (lumbar spine T-score, −2.6; femoral neck T-score, −2.9). For this reason, the patient underwent treatment with oral alendronate (70 mg/week)
Clin Rheumatol
Fig. 1 Erythrocyte sedimentation rate (ESR), serum amyloid-A (SAA), and C-reactive protein (CRP) serum levels during the entire follow-up, pointing-up correlations with treatments, and disease exacerbations. CRP serum levels have been multiplied by 102 in order to allow a better graphical representation; for the same reason, the first ESR and CRP
serum levels have been indicated beside their respective lines rather than shown precisely on the graph. The unit of measure used for y-axis depends on the laboratory data shown (mm/h for ESR, mg/L for SAA, mg/dL × 102 for CRP), while the numbers indicated on x-axis show the months of follow-up since May 2009
along with canakinumab. Unexpectedly, she experienced a clinical amelioration after only 2 days of treatment, and no further inflammatory attacks have occurred over the following 6 months. In addition, the inflammatory parameters erythrosedimentation rate (ESR), serum amyloid-A (SAA), and C-reactive protein (CRP), checked monthly, turned back to normal. Figure 1 shows the ESR, SAA, and CRP before and after alendronate administration. Unfortunately, after 7 months, the onset of gastrointestinal intolerance required alendronate withdrawal at the follow-up visit. Strikingly, despite canakinumab therapy, 7 weeks after alendronate interruption, a further disease relapse with lowgrade fever, abdominal discomfort, and severe myalgia recurred. The patient is currently being treated with canakinumab (150 mg every 4 weeks) and medium-dose prednisone “on demand.” Management of TRAPS is more challenging than in other autoinflammatory syndromes, due to both wide genetic heterogeneity and protean clinical phenotype [2]. At first, etanercept, a recombinant human TNF receptor (p75)-Fc fusion protein, was the mainstay of treatment [3]. IL-1 inhibitors have been shown to induce a longer-lasting effect in controlling TRAPS manifestations and also a more stable normalization of acute-phase reactants [4, 5]. Our surprising result on the overall TRAPS clinical course obtained with oral alendronate, given to control osteoporosis and prevent bone fractures, might be due to the anti-inflammatory properties of nitrogen-containing bisphosphonates, acting on the chronic inflammatory
component of TRAPS itself. In fact, bisphosphonates have revealed anti-inflammatory effects, hindering nitric oxide production in a dose-dependent manner in macrophages [6]. In addition, the induction of apoptosis exerted by different bisphosphonates may have a central role to elucidate their anti-inflammatory effects [7]. On the other hand, bisphosphonates determine a significant depletion in synovial lining macrophages and local reduction of proinflammatory cytokines [8]; in particular, alendronate has been reported to inhibit lipopolysaccharide-induced generation of IL-1β, IL-6, and TNF-α in human monocytes [9]. Since the V95M mutation has been found in patients with a mild TRAPS phenotype [10], a spontaneous disease amelioration cannot be excluded. However, this is not the first case report describing a patient affected with an autoinflammatory disorder responsive to alendronate administration. In fact, a patient affected with mevalonate kinase deficiency (MKD), carrying a homozygous lowpenetrance V377I mutation, has recently shown a complete clinical and laboratory remission soon after alendronate administration. In addition, alendronate discontinuation brought about a typical MKD fever attack, while alendronate resumption during a prolonged fever episode led to the resolution of the attack, strengthening the role of alendronate in this patient [11]. However, in spite of the remarkable results, both this reported TRAPS patient and the one with MVK were suffering from a mild disease variant. It would be interesting to evaluate alendronate treatment also in
Clin Rheumatol
patients carrying high-penetrance mutations, in order to establish if similar beneficial results might be obtained in the presence of severe disease variants with increased disease activity. Notably, our patient showed a partial loss of canakinumab efficacy rather than a complete disease relapse when alendronate was introduced. Certainly, further clinical studies should be performed on a larger number of patients in order to clarify bisphosphonates’ role in the intricate scenery of autoinflammatory disorders. If our results will be confirmed, it will be also interesting to unravel the underlying bisphosphonate mechanism of action. Disclosures Luca Cantarini received grant/research support from Novartis and SOBI and is a consultant for Novartis and SOBI.
References 1. McDermott MF, Aksentijevich I, Galon J, McDermott EM, Ogunkolade BW, Centola M 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 97:133–144 2. Cantarini L, Lucherini OM, Muscari I, Frediani B, Galeazzi M, Brizi MG et al (2012) Tumour necrosis factor receptor-associated periodic
syndrome (TRAPS): state of the art and future perspectives. Autoimmun Rev 12:38–43 3. Cantarini L, Rigante D, Lucherini OM, Cimaz R, Laghi Pasini F, Baldari CT 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 23:701–707 4. Vitale A, Rigante D, Lucherini OM, Caso F, Muscari I, Magnotti F et al (2013) Biological treatments: new weapons in the management of monogenic autoinflammatory disorders. Mediat Inflamm 2013:939847 5. Brizi MG, Galeazzi M, Lucherini OM, Cantarini L, Cimaz R (2012) Successful treatment of tumor necrosis factor receptor-associated periodic syndrome with canakinumab. Ann Intern Med 156:907–908 6. Romas E, Gillespie MT (2006) Inflammation-induced bone loss: can it be prevented? Rheum Dis Clin N Am 32:759–773 7. Bodar EJ, van der Hilst JC, van Heerde W, van der Meer JW, Drenth JP, Simon A (2007) Defective apoptosis of peripheral-blood lymphocytes in hyper-IgD and periodic fever syndrome. Blood 109:2416–2418 8. Cantatore FP, Introsso AM, Carrozzo M (1996) Effects of bisphosphonates on interleukin 1, tumor necrosis factor alpha, and beta 2 microglobulin in rheumatoid arthritis. J Rheumatol 23:1117–1118 9. Sansoni P, Passeri G, Fagnoni F, Mohagheghpour N, Snelli G, Brianti V et al (1995) Inhibition of antigen-presenting cell function by alendronate in vitro. J Bone Miner Res 10:1719–1725 10. Cantarini L, Rigante D, Merlini G, Vitale A, Caso F, Lucherini OM et al (2013) 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. doi:10.1016/j.semarthrit.2013.12.002 11. Cantarini L, Vitale A, Magnotti F, Lucherini OM, Caso F, Frediani B, Galeazzi M, Rigante D (2013) Weekly oral alendronate in mevalonate kinase deficiency. Orphanet J Rare Dis 8:196
