Beneficial response to interleukin 1 receptor antagonist in traps

Abstract

Interleukin 1 is one of the central proinflammatory cytokines, and it has been implicated in in vitro studies as an important pathogenic factor in several autoinflammatory syndromes (1Chae J.J. Komarow H.D. Cheng J. et al.Targeted disruption of pyrin, the FMF protein, causes heightened sensitivity to en.Mol Cell. 2003; 11: 591-604Abstract Full Text Full Text PDF PubMed Scopus (349) Google Scholar, 2Frenkel J. Rijkers G.T. Mandey S.H. et al.Lack of isoprenoid products raises ex vivo interleukin-1beta secretion in hyperimmunoglobulinemia D and periodic fever syndrome.Arthritis Rheum. 2002; 46: 2794-2803Crossref PubMed Scopus (151) Google Scholar, 3Aksentijevich I. Nowak M. Mallah M. et al.De novo CIAS1 mutations, cytokine activation, and evidence for genetic heterogeneity in patients with neonatal-onset multisystem inflammatory disease (NOMID): A new member of the expanding family of pyrin-associated autoinflammatory diseases.Arthritis Rheum. 2002; 46: 3340-3348Crossref PubMed Scopus (588) Google Scholar). Hawkins et al reported good results with the recombinant interleukin 1–receptor antagonist anakinra (4Nuki G. Bresnihan B. Bear M.B. McCabe D. Long-term safety and maintenance of clinical improvement following treatment with anakinra (recombinant human interleukin-1 receptor antagonist) in patients with rheumatoid arthritis: extension phase of a randomized, double-blind, placebo-controlled trial.Arthritis Rheum. 2002; 46: 2838-2846Crossref PubMed Scopus (205) Google Scholar) in 2 patients with Muckle-Wells syndrome, which is one of the autoinflammatory syndromes (5Hawkins P.N. Lachmann H.J. McDermott M.F. Interleukin-1-receptor antagonist in the Muckle-Wells syndrome.N Engl J Med. 2003; 348: 2583-2584Crossref PubMed Scopus (391) Google Scholar). This prompted us to try anakinra in a patient with severe, treatment-resistant tumor necrosis factor (TNF) receptor–associated periodic syndrome (TRAPS) (Mendelian Inheritance in Man #142680).The patient, a 19-year-old Dutch woman, was diagnosed with TRAPS confirmed by a C43Y-mutation in the TNF-receptor type 1 (TNFRSF1A) gene. From the age of 1 year she had episodes of fever, general malaise, abdominal pain, myalgia, and painful erythematous skin lesions, accompanied by vigorous acute phase response. Numerous therapies were tried, including nonsteroidal antiinflammatory drugs (NSAIDs), methotrexate, and cyclosporin, with disappointing results. The only reasonably effective drug was prednisone (at least 30 mg daily). After the diagnosis was made, she started with the TNF-inhibitor etanercept (6Drewe E. McDermott E.M. Powell P.T. et al.Prospective study of anti-tumour necrosis factor receptor superfamily 1B fusion protein, and case study of anti-tumour necrosis factor receptor superfamily 1A fusion protein, in tumour necrosis factor receptor associated periodic syndrome (TRAPS): clinical and laboratory findings in a series of seven patients.Rheumatology (Oxford). 2003; 42: 235-239Crossref PubMed Scopus (178) Google Scholar), which improved symptoms temporarily, but the acute phase response persisted and prednisone could not be tapered. A brief trial of sirolimus, an inhibitor of T-cell activation (7Drewe E. Powell R.J. Novel treatment for tumour necrosis factor receptor associated periodic syndrome (TRAPS): case history of experience with infliximab and sirolimus post etanercept.Clin Exp Rheumatol. 2002; 20 (abstract): S71PubMed Google Scholar), had to be stopped because of severe allergic reaction. In the previous year, inflammatory symptoms had become unremitting and occurred daily. Between July 2002 and November 2003 (total: 22 measurements), median C-reactive protein concentration was 117.5 mg/L (interquartile range, 70.5 to 157.5 mg/L) and the leukocyte count was 20.9 x 109/L (interquartile range, 14.9 to 23.6 x 109/L). The patient consented to the use of anakinra given subcutaneously at a dose of 100 mg daily, which resulted in remarkable improvement of symptoms and an unprecedented decrease of C-reactive protein concentration and leukocyte count within days (Figure 1). Prednisone was rapidly tapered to 10 mg daily. After 1 month, the patient was symptom-free and feeling well for the first time in many years. However, she did suffer pain and redness at the site of the anakinra injection (Figure 2).Figure 2Erythematous and painful injection site reaction associated with subcutaneous use of anakinra on the upper leg of the patient. Such reactions clear up after a few days, and are less severe when anakinra is used in the abdominal region.View Large Image Figure ViewerDownload (PPT)Tumor necrosis factor receptor–associated periodic syndrome is a hereditary autoinflammatory syndrome caused by TNFRSF1A gene mutations and characterized by recurrent episodes of fever and inflammation. Its clinical features can vary greatly among patients, from recurrent, mild, localized myalgia to the incapacitating, severe symptoms described in this patient (8Hull K.M. Drewe E. Aksentijevich I. et al.The TNF receptor-associated periodic syndrome (TRAPS): emerging concepts of an autoinflammatory disorder.Medicine (Baltimore). 2002; 81: 349-368Crossref PubMed Scopus (369) Google Scholar). In mild cases, the occasional use of NSAIDs is usually sufficient for management of symptoms. After the discovery of the genetic etiology, anti-TNF treatment in the form of etanercept has been introduced and found to be successful in many cases (6Drewe E. McDermott E.M. Powell P.T. et al.Prospective study of anti-tumour necrosis factor receptor superfamily 1B fusion protein, and case study of anti-tumour necrosis factor receptor superfamily 1A fusion protein, in tumour necrosis factor receptor associated periodic syndrome (TRAPS): clinical and laboratory findings in a series of seven patients.Rheumatology (Oxford). 2003; 42: 235-239Crossref PubMed Scopus (178) Google Scholar, 8Hull K.M. Drewe E. Aksentijevich I. et al.The TNF receptor-associated periodic syndrome (TRAPS): emerging concepts of an autoinflammatory disorder.Medicine (Baltimore). 2002; 81: 349-368Crossref PubMed Scopus (369) Google Scholar, 9Simon A. van Deuren M. Tighe P.J. et al.Genetic analysis as a valuable key to diagnosis and treatment of periodic Fever.Arch Intern Med. 2001; 161: 2491-2493Crossref PubMed Scopus (25) Google Scholar). Not all patients benefit, however, and initial response may wear off with prolonged therapy, necessitating alternative therapies. In one severe case unresponsive to etanercept, Drewe et al (7Drewe E. Powell R.J. Novel treatment for tumour necrosis factor receptor associated periodic syndrome (TRAPS): case history of experience with infliximab and sirolimus post etanercept.Clin Exp Rheumatol. 2002; 20 (abstract): S71PubMed Google Scholar) describe a beneficial response to sirolimus. This could not be used in our patient because of an allergic reaction.Anakinra is a recombinant form of interleukin 1ra, an endogenous inhibitor of interleukin 1 signaling, that is used in the treatment of rheumatoid arthritis (4Nuki G. Bresnihan B. Bear M.B. McCabe D. Long-term safety and maintenance of clinical improvement following treatment with anakinra (recombinant human interleukin-1 receptor antagonist) in patients with rheumatoid arthritis: extension phase of a randomized, double-blind, placebo-controlled trial.Arthritis Rheum. 2002; 46: 2838-2846Crossref PubMed Scopus (205) Google Scholar). It is usually well tolerated; the most common side effect is an injection-site reaction with pain, erythema, and local inflammation (10Fleischmann R.M. Addressing the safety of anakinra in patients with rheumatoid arthritis.Rheumatology (Oxford). 2003; 42: ii29-ii35PubMed Google Scholar). The beneficial response to anakinra argues for a central role of interleukin 1 in the pathogenesis TRAPS (1Chae J.J. Komarow H.D. Cheng J. et al.Targeted disruption of pyrin, the FMF protein, causes heightened sensitivity to en.Mol Cell. 2003; 11: 591-604Abstract Full Text Full Text PDF PubMed Scopus (349) Google Scholar, 2Frenkel J. Rijkers G.T. Mandey S.H. et al.Lack of isoprenoid products raises ex vivo interleukin-1beta secretion in hyperimmunoglobulinemia D and periodic fever syndrome.Arthritis Rheum. 2002; 46: 2794-2803Crossref PubMed Scopus (151) Google Scholar, 3Aksentijevich I. Nowak M. Mallah M. et al.De novo CIAS1 mutations, cytokine activation, and evidence for genetic heterogeneity in patients with neonatal-onset multisystem inflammatory disease (NOMID): A new member of the expanding family of pyrin-associated autoinflammatory diseases.Arthritis Rheum. 2002; 46: 3340-3348Crossref PubMed Scopus (588) Google Scholar, 5Hawkins P.N. Lachmann H.J. McDermott M.F. Interleukin-1-receptor antagonist in the Muckle-Wells syndrome.N Engl J Med. 2003; 348: 2583-2584Crossref PubMed Scopus (391) Google Scholar). It is generally assumed that in this syndrome the inflammatory effects of TNF-α and lymphotoxin are not countered adequately, because of a lack of a soluble TNF-receptor, the major inhibitor of TNF. In that respect, it is hard to understand that the TNF-receptor construct, etanercept, had hardly any therapeutic effect in our patient. Perhaps even more difficult to explain is the effectiveness of interleukin 1ra, since interleukin 1β and interleukin 1α are responsible for only a small part of the biological effects of TNF-α and lymphotoxin. Further research is required and long-term efficacy must be determined. Interleukin 1 is one of the central proinflammatory cytokines, and it has been implicated in in vitro studies as an important pathogenic factor in several autoinflammatory syndromes (1Chae J.J. Komarow H.D. Cheng J. et al.Targeted disruption of pyrin, the FMF protein, causes heightened sensitivity to en.Mol Cell. 2003; 11: 591-604Abstract Full Text Full Text PDF PubMed Scopus (349) Google Scholar, 2Frenkel J. Rijkers G.T. Mandey S.H. et al.Lack of isoprenoid products raises ex vivo interleukin-1beta secretion in hyperimmunoglobulinemia D and periodic fever syndrome.Arthritis Rheum. 2002; 46: 2794-2803Crossref PubMed Scopus (151) Google Scholar, 3Aksentijevich I. Nowak M. Mallah M. et al.De novo CIAS1 mutations, cytokine activation, and evidence for genetic heterogeneity in patients with neonatal-onset multisystem inflammatory disease (NOMID): A new member of the expanding family of pyrin-associated autoinflammatory diseases.Arthritis Rheum. 2002; 46: 3340-3348Crossref PubMed Scopus (588) Google Scholar). Hawkins et al reported good results with the recombinant interleukin 1–receptor antagonist anakinra (4Nuki G. Bresnihan B. Bear M.B. McCabe D. Long-term safety and maintenance of clinical improvement following treatment with anakinra (recombinant human interleukin-1 receptor antagonist) in patients with rheumatoid arthritis: extension phase of a randomized, double-blind, placebo-controlled trial.Arthritis Rheum. 2002; 46: 2838-2846Crossref PubMed Scopus (205) Google Scholar) in 2 patients with Muckle-Wells syndrome, which is one of the autoinflammatory syndromes (5Hawkins P.N. Lachmann H.J. McDermott M.F. Interleukin-1-receptor antagonist in the Muckle-Wells syndrome.N Engl J Med. 2003; 348: 2583-2584Crossref PubMed Scopus (391) Google Scholar). This prompted us to try anakinra in a patient with severe, treatment-resistant tumor necrosis factor (TNF) receptor–associated periodic syndrome (TRAPS) (Mendelian Inheritance in Man #142680). The patient, a 19-year-old Dutch woman, was diagnosed with TRAPS confirmed by a C43Y-mutation in the TNF-receptor type 1 (TNFRSF1A) gene. From the age of 1 year she had episodes of fever, general malaise, abdominal pain, myalgia, and painful erythematous skin lesions, accompanied by vigorous acute phase response. Numerous therapies were tried, including nonsteroidal antiinflammatory drugs (NSAIDs), methotrexate, and cyclosporin, with disappointing results. The only reasonably effective drug was prednisone (at least 30 mg daily). After the diagnosis was made, she started with the TNF-inhibitor etanercept (6Drewe E. McDermott E.M. Powell P.T. et al.Prospective study of anti-tumour necrosis factor receptor superfamily 1B fusion protein, and case study of anti-tumour necrosis factor receptor superfamily 1A fusion protein, in tumour necrosis factor receptor associated periodic syndrome (TRAPS): clinical and laboratory findings in a series of seven patients.Rheumatology (Oxford). 2003; 42: 235-239Crossref PubMed Scopus (178) Google Scholar), which improved symptoms temporarily, but the acute phase response persisted and prednisone could not be tapered. A brief trial of sirolimus, an inhibitor of T-cell activation (7Drewe E. Powell R.J. Novel treatment for tumour necrosis factor receptor associated periodic syndrome (TRAPS): case history of experience with infliximab and sirolimus post etanercept.Clin Exp Rheumatol. 2002; 20 (abstract): S71PubMed Google Scholar), had to be stopped because of severe allergic reaction. In the previous year, inflammatory symptoms had become unremitting and occurred daily. Between July 2002 and November 2003 (total: 22 measurements), median C-reactive protein concentration was 117.5 mg/L (interquartile range, 70.5 to 157.5 mg/L) and the leukocyte count was 20.9 x 109/L (interquartile range, 14.9 to 23.6 x 109/L). The patient consented to the use of anakinra given subcutaneously at a dose of 100 mg daily, which resulted in remarkable improvement of symptoms and an unprecedented decrease of C-reactive protein concentration and leukocyte count within days (Figure 1). Prednisone was rapidly tapered to 10 mg daily. After 1 month, the patient was symptom-free and feeling well for the first time in many years. However, she did suffer pain and redness at the site of the anakinra injection (Figure 2). Tumor necrosis factor receptor–associated periodic syndrome is a hereditary autoinflammatory syndrome caused by TNFRSF1A gene mutations and characterized by recurrent episodes of fever and inflammation. Its clinical features can vary greatly among patients, from recurrent, mild, localized myalgia to the incapacitating, severe symptoms described in this patient (8Hull K.M. Drewe E. Aksentijevich I. et al.The TNF receptor-associated periodic syndrome (TRAPS): emerging concepts of an autoinflammatory disorder.Medicine (Baltimore). 2002; 81: 349-368Crossref PubMed Scopus (369) Google Scholar). In mild cases, the occasional use of NSAIDs is usually sufficient for management of symptoms. After the discovery of the genetic etiology, anti-TNF treatment in the form of etanercept has been introduced and found to be successful in many cases (6Drewe E. McDermott E.M. Powell P.T. et al.Prospective study of anti-tumour necrosis factor receptor superfamily 1B fusion protein, and case study of anti-tumour necrosis factor receptor superfamily 1A fusion protein, in tumour necrosis factor receptor associated periodic syndrome (TRAPS): clinical and laboratory findings in a series of seven patients.Rheumatology (Oxford). 2003; 42: 235-239Crossref PubMed Scopus (178) Google Scholar, 8Hull K.M. Drewe E. Aksentijevich I. et al.The TNF receptor-associated periodic syndrome (TRAPS): emerging concepts of an autoinflammatory disorder.Medicine (Baltimore). 2002; 81: 349-368Crossref PubMed Scopus (369) Google Scholar, 9Simon A. van Deuren M. Tighe P.J. et al.Genetic analysis as a valuable key to diagnosis and treatment of periodic Fever.Arch Intern Med. 2001; 161: 2491-2493Crossref PubMed Scopus (25) Google Scholar). Not all patients benefit, however, and initial response may wear off with prolonged therapy, necessitating alternative therapies. In one severe case unresponsive to etanercept, Drewe et al (7Drewe E. Powell R.J. Novel treatment for tumour necrosis factor receptor associated periodic syndrome (TRAPS): case history of experience with infliximab and sirolimus post etanercept.Clin Exp Rheumatol. 2002; 20 (abstract): S71PubMed Google Scholar) describe a beneficial response to sirolimus. This could not be used in our patient because of an allergic reaction. Anakinra is a recombinant form of interleukin 1ra, an endogenous inhibitor of interleukin 1 signaling, that is used in the treatment of rheumatoid arthritis (4Nuki G. Bresnihan B. Bear M.B. McCabe D. Long-term safety and maintenance of clinical improvement following treatment with anakinra (recombinant human interleukin-1 receptor antagonist) in patients with rheumatoid arthritis: extension phase of a randomized, double-blind, placebo-controlled trial.Arthritis Rheum. 2002; 46: 2838-2846Crossref PubMed Scopus (205) Google Scholar). It is usually well tolerated; the most common side effect is an injection-site reaction with pain, erythema, and local inflammation (10Fleischmann R.M. Addressing the safety of anakinra in patients with rheumatoid arthritis.Rheumatology (Oxford). 2003; 42: ii29-ii35PubMed Google Scholar). The beneficial response to anakinra argues for a central role of interleukin 1 in the pathogenesis TRAPS (1Chae J.J. Komarow H.D. Cheng J. et al.Targeted disruption of pyrin, the FMF protein, causes heightened sensitivity to en.Mol Cell. 2003; 11: 591-604Abstract Full Text Full Text PDF PubMed Scopus (349) Google Scholar, 2Frenkel J. Rijkers G.T. Mandey S.H. et al.Lack of isoprenoid products raises ex vivo interleukin-1beta secretion in hyperimmunoglobulinemia D and periodic fever syndrome.Arthritis Rheum. 2002; 46: 2794-2803Crossref PubMed Scopus (151) Google Scholar, 3Aksentijevich I. Nowak M. Mallah M. et al.De novo CIAS1 mutations, cytokine activation, and evidence for genetic heterogeneity in patients with neonatal-onset multisystem inflammatory disease (NOMID): A new member of the expanding family of pyrin-associated autoinflammatory diseases.Arthritis Rheum. 2002; 46: 3340-3348Crossref PubMed Scopus (588) Google Scholar, 5Hawkins P.N. Lachmann H.J. McDermott M.F. Interleukin-1-receptor antagonist in the Muckle-Wells syndrome.N Engl J Med. 2003; 348: 2583-2584Crossref PubMed Scopus (391) Google Scholar). It is generally assumed that in this syndrome the inflammatory effects of TNF-α and lymphotoxin are not countered adequately, because of a lack of a soluble TNF-receptor, the major inhibitor of TNF. In that respect, it is hard to understand that the TNF-receptor construct, etanercept, had hardly any therapeutic effect in our patient. Perhaps even more difficult to explain is the effectiveness of interleukin 1ra, since interleukin 1β and interleukin 1α are responsible for only a small part of the biological effects of TNF-α and lymphotoxin. Further research is required and long-term efficacy must be determined.