bs_bs_banner
Clinical and Experimental Immunology
I M M U N O M O D U L AT I O N
doi:10.1111/cei.12533
7th International Immunoglobulin Conference: Immunomodulation
M. G. Danieli* and Y. Shoenfeld† *Università Politecnica delle Marche, Ancona, Italy, and †Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
Correspondence: M. G. Danieli. E-mail: [email protected]
Summary Immunomodulation uses synthetic, natural and recombinant preparations to modify the immune response to a desired level, typically to treat specific autoimmune diseases, as will be discussed in this section. Rheumatoid arthritis (RA) is a common systemic autoimmune disease, affecting 1% of the population worldwide. Currently, a first-line disease-modifying therapy for RA is methotrexate; however, more than 40 monoclonal antibodies are in use or under investigation for the treatment of RA. This panoply of biological disease-modifying agents means that clinicians can make use of drugs with different mechanisms of action should one type become ineffective. In autoimmune pemphigus conditions, identification of pathogenic autoantibodies against intercellular cadherin desmoglein 1 and/or 3 antigens is one of the criteria for appropriate diagnosis. In pemphigoid conditions, autoantibodies are directed against bullous pemphigoid antigens BP230 and BP180, and in both types of immunobullous disease intravenous immunoglobulin (IVIg), as adjuvant therapy in combination with a cytotoxic drug, is effective in reducing autoantibody levels, disease severity and background steroid use. Further studies are required to establish the role of monoclonal antibodies in the treatment of autoimmune bullous disease. IVIg may also be effective in another at-risk population with autoimmune disease, namely secondary recurrent miscarriage (RM). However, the mechanism of action of IVIg in secondary RM is largely unknown, although levels of natural killer cell biomarkers, particularly CD56+, have been shown to decline after IVIg treatment [1–6]. Data from meta-analyses of heterogeneous placebo-controlled trials indicate that IVIg may be effective in secondary RM, but most trials to date have used immunomodulatory doses lower than those considered to be efficient in autoimmune disease. The results of a recently completed study may help to address this question. Keywords: autoantibodies, immunobullous skin disease, intravenous immunoglobulin, recurrent miscarriage, rheumatoid arthritis
Introduction Intravenous immunoglobulin (IVIg) is a blood product containing immunoglobulin (Ig)G from healthy subjects, used as an immunomodulatory agent in several immunemediated disorders, ranging from thrombotic thrombocytopenic purpura to idiopathic inflammatory myopathies and inflammatory bowel diseases [7–13]. Many different pathophysiological mechanisms and modalities of action of Ig are involved in IVIg interaction with the immune system 112
[14,15], so it is not surprising that IVIg can positively influence the outcome of several immune-mediated diseases. The advantages of IVIg treatment include steroid-sparing effects and the possibility to withdraw immunosuppressants [16]. This session, chaired by Professor M. Giovanna Danieli and Professor Yehuda Shoenfeld, focuses on immunomodulation with antibodies or IVIg in conditions that have received less attention in the Ig community than primary immunodeficiencies or neurological disorders,
© 2014 British Society for Immunology, Clinical and Experimental Immunology, 178: 112–114
Immunomodulation
including rheumatoid arthritis (RA), immunobullous autoimmune conditions and anti-fetal immunity, particularly recurrent miscarriage (RM). Dr Gottenberg’s presentation focuses on RA, the most frequent autoimmune disease. It has a prevalence of approximately 1% of the global population [17], and may be associated with severe lymphoproliferative malignancies (i.e. lymphomas). Dr Gottenberg highlights the importance of early diagnosis and aggressive treatment of RA before joint destruction becomes devastating for the patient [18]. He outlines the therapeutic strategy in his centre including methotrexate alone as first-line treatment with the addition of biological disease-modifying drugs if required, and highlights potential risks identified from accumulated data in the French registry. Autoimmune bullous disease, another group of debilitating autoimmune diseases, is described by Dr Czernik [19]. Patients respond to IVIg with rapid lowering of the levels of pathogenic autoantibodies, and Dr Czernik presents data from a number of studies evaluating the effect of IVIg alone or in combination with immunosuppressants or rituximab in these rare conditions. Dr Christiansen presents data to show that IVIg has another potentially important role in the treatment of secondary RM, a condition associated with raised tumour necrosis factor (TNF)-α and specific maternal human leucocyte antigen (HLA) polymorphisms. The doses of IVIg used in this condition are usually lower than in other autoimmune diseases [20]. Despite considerable heterogeneity between trials, a meta-analysis of placebo-controlled studies of IVIg in patients with secondary RM almost reached statistical significance in favour of IVIg. The results of a large randomized, double-blind, placebo-controlled study in 82 patients with secondary RM are awaited with interest [21,22]. IVIg administration of Ig remains a feasible therapeutic option in patients with autoimmune disorders. The low rate of side effects, which improves quality of life, the possibility to withdraw the immunosuppressants and the steroidsparing effect make IVIg a viable option in selected patients with immune-mediated disorders when standard therapeutic regimens fail or when immunosuppressants are contraindicated.
Acknowledgements M. G. D. and Y. S. would like to thank Meridian HealthComms Ltd for providing medical writing services.
Disclosures M. G. D. has received an honorary fee from CSL Behring. Y. S. has received consulting support and grants from LFB and OMRIX.
References 1 Kwak JY, Kwak FM, Ainbinder SW, Ruiz AM, Beer AE. Elevated peripheral blood natural killer cells are effectively downregulated by immunoglobulin G infusion in women with recurrent spontaneous abortions. Am J Reprod Immunol 1996; 35:363–9. 2 Moraru M, Carbone J, Alecsandru D et al. Intravenous immunoglobulin treatment increased live birth rate in a Spanish cohort of women with recurrent reproductive failure and expanded CD56(+) cells. Am J Reprod Immunol 2012; 68:75–84. 3 Perricone R, Di Muzio G, Perricone C et al. High levels of peripheral blood NK cells in women suffering from recurrent spontaneous abortion are reverted from high-dose intravenous immunoglobulins. Am J Reprod Immunol 2006; 55:232–9. 4 Rigal D, Vermot-Desroches C, Heitz S, Bernaud J, Alfonsi F, Monier JC. Effects of intravenous immunoglobulins (IVIG) on peripheral blood B, NK, and T cell subpopulations in women with recurrent spontaneous abortions: specific effects on LFA-1 and CD56 molecules. Clin Immunol Immunopathol 1994; 71:309–14. 5 Roussev RG, Ng SC, Coulam CB. Natural killer cell functional activity suppression by intravenous immunoglobulin, intralipid and soluble human leukocyte antigen-G. Am J Reprod Immunol 2007; 57:262–9. 6 Ruiz JE, Kwak JY, Baum L et al. Intravenous immunoglobulin inhibits natural killer cell activity in vivo in women with recurrent spontaneous abortion. Am J Reprod Immunol 1996; 35:370–5. 7 Berman H, Rodríguez-Pintó I, Cervera R et al. Rituximab use in the catastrophic antiphospholipid syndrome: descriptive analysis of the CAPS registry patients receiving rituximab. Autoimmun Rev 2013; 12:1085–90. 8 Danieli MG, Gambini S, Pettinari L, Logullo F, Veronesi G, Gabrielli A. Impact of treatment on survival in polymyositis and dermatomyositis. A single-centre long-term follow-up study. Autoimmun Rev 2014; 13:1048–54. 9 Goebel A, Blaes F. Complex regional pain syndrome, prototype of a novel kind of autoimmune disease. Autoimmun Rev 2013; 12:682–6. 10 Lo E, Deane S. Diagnosis and classification of immune-mediated thrombocytopenia. Autoimmun Rev 2014; 13:577–83. 11 Rogosnitzky M, Danks R, Holt D. Intravenous immunoglobulin for the treatment of Crohn’s disease. Autoimmun Rev 2012; 12:275–80. 12 Ruffatti A, Marson P, Svaluto-Moreolo G et al. A combination therapy protocol of plasmapheresis, intravenous immunoglobulins and betamethasone to treat anti-Ro/La-related congenital atrioventricular block. A case series and review of the literature. Autoimmun Rev 2013; 12:768–73. 13 Saadoun D, Bodaghi B, Bienvenu B et al. Biotherapies in inflammatory ocular disorders: interferons, immunoglobulins, monoclonal antibodies. Autoimmun Rev 2013; 12:774–83. 14 Cousens LP, Tassone R, Mazer BD, Ramachandiran V, Scott DW, De Groot AS. Tregitope update: mechanism of action parallels IVIg. Autoimmun Rev 2013; 12:436–43. 15 Kaveri SV. Intravenous immunoglobulin: exploiting the potential of natural antibodies. Autoimmun Rev 2012; 11:792–4. 16 Danieli MG, Calcabrini L, Calabrese V, Marchetti A, Logullo F, Gabrielli A. Intravenous immunoglobulin as add on treatment with mycophenolate mofetil in severe myositis. Autoimmun Rev 2009; 9:124–7.
© 2014 British Society for Immunology, Clinical and Experimental Immunology, 178: 112–114
113
M. G. Danieli & Y. Shoenfeld 17 Gibofsky A. Epidemiology, pathophysiology, and diagnosis of rheumatoid arthritis: a synopsis. Am J Manag Care 2014; 20:s128– 45. 18 Atzeni F, Benucci M, Salli S, Bongiovanni S, Boccassini L, Sarzi-Puttini P. Different effects of biological drugs in rheumatoid arthritis. Autoimmun Rev 2013; 12:575–9. 19 Sticherling M, Erfurt-Berge C. Autoimmune blistering diseases of the skin. Autoimmun Rev 2012; 11:226–30. 20 Comarmond C, Cacoub P. Antiphospholipid syndrome: from pathogenesis to novel immunomodulatory therapies. Autoimmun Rev 2013; 12:752–7.
114
21 Clark DA. Intravenous immunoglobulin and idiopathic secondary recurrent miscarriage: methodological problems. Hum Reprod 2011; 26:2586–7; author reply 7–9. 22 Hutton B, Sharma R, Fergusson D et al. Use of intravenous immunoglobulin for treatment of recurrent miscarriage: a systematic review. Br J Obstet Gynaecol 2007; 114:134–42.
© 2014 British Society for Immunology, Clinical and Experimental Immunology, 178: 112–114
This document is a scanned copy of a printed document. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material.
Clinical and Experimental Immunology
I M M U N O M O D U L AT I O N
doi:10.1111/cei.12533
7th International Immunoglobulin Conference: Immunomodulation
M. G. Danieli* and Y. Shoenfeld† *Università Politecnica delle Marche, Ancona, Italy, and †Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
Correspondence: M. G. Danieli. E-mail: [email protected]
Summary Immunomodulation uses synthetic, natural and recombinant preparations to modify the immune response to a desired level, typically to treat specific autoimmune diseases, as will be discussed in this section. Rheumatoid arthritis (RA) is a common systemic autoimmune disease, affecting 1% of the population worldwide. Currently, a first-line disease-modifying therapy for RA is methotrexate; however, more than 40 monoclonal antibodies are in use or under investigation for the treatment of RA. This panoply of biological disease-modifying agents means that clinicians can make use of drugs with different mechanisms of action should one type become ineffective. In autoimmune pemphigus conditions, identification of pathogenic autoantibodies against intercellular cadherin desmoglein 1 and/or 3 antigens is one of the criteria for appropriate diagnosis. In pemphigoid conditions, autoantibodies are directed against bullous pemphigoid antigens BP230 and BP180, and in both types of immunobullous disease intravenous immunoglobulin (IVIg), as adjuvant therapy in combination with a cytotoxic drug, is effective in reducing autoantibody levels, disease severity and background steroid use. Further studies are required to establish the role of monoclonal antibodies in the treatment of autoimmune bullous disease. IVIg may also be effective in another at-risk population with autoimmune disease, namely secondary recurrent miscarriage (RM). However, the mechanism of action of IVIg in secondary RM is largely unknown, although levels of natural killer cell biomarkers, particularly CD56+, have been shown to decline after IVIg treatment [1–6]. Data from meta-analyses of heterogeneous placebo-controlled trials indicate that IVIg may be effective in secondary RM, but most trials to date have used immunomodulatory doses lower than those considered to be efficient in autoimmune disease. The results of a recently completed study may help to address this question. Keywords: autoantibodies, immunobullous skin disease, intravenous immunoglobulin, recurrent miscarriage, rheumatoid arthritis
Introduction Intravenous immunoglobulin (IVIg) is a blood product containing immunoglobulin (Ig)G from healthy subjects, used as an immunomodulatory agent in several immunemediated disorders, ranging from thrombotic thrombocytopenic purpura to idiopathic inflammatory myopathies and inflammatory bowel diseases [7–13]. Many different pathophysiological mechanisms and modalities of action of Ig are involved in IVIg interaction with the immune system 112
[14,15], so it is not surprising that IVIg can positively influence the outcome of several immune-mediated diseases. The advantages of IVIg treatment include steroid-sparing effects and the possibility to withdraw immunosuppressants [16]. This session, chaired by Professor M. Giovanna Danieli and Professor Yehuda Shoenfeld, focuses on immunomodulation with antibodies or IVIg in conditions that have received less attention in the Ig community than primary immunodeficiencies or neurological disorders,
© 2014 British Society for Immunology, Clinical and Experimental Immunology, 178: 112–114
Immunomodulation
including rheumatoid arthritis (RA), immunobullous autoimmune conditions and anti-fetal immunity, particularly recurrent miscarriage (RM). Dr Gottenberg’s presentation focuses on RA, the most frequent autoimmune disease. It has a prevalence of approximately 1% of the global population [17], and may be associated with severe lymphoproliferative malignancies (i.e. lymphomas). Dr Gottenberg highlights the importance of early diagnosis and aggressive treatment of RA before joint destruction becomes devastating for the patient [18]. He outlines the therapeutic strategy in his centre including methotrexate alone as first-line treatment with the addition of biological disease-modifying drugs if required, and highlights potential risks identified from accumulated data in the French registry. Autoimmune bullous disease, another group of debilitating autoimmune diseases, is described by Dr Czernik [19]. Patients respond to IVIg with rapid lowering of the levels of pathogenic autoantibodies, and Dr Czernik presents data from a number of studies evaluating the effect of IVIg alone or in combination with immunosuppressants or rituximab in these rare conditions. Dr Christiansen presents data to show that IVIg has another potentially important role in the treatment of secondary RM, a condition associated with raised tumour necrosis factor (TNF)-α and specific maternal human leucocyte antigen (HLA) polymorphisms. The doses of IVIg used in this condition are usually lower than in other autoimmune diseases [20]. Despite considerable heterogeneity between trials, a meta-analysis of placebo-controlled studies of IVIg in patients with secondary RM almost reached statistical significance in favour of IVIg. The results of a large randomized, double-blind, placebo-controlled study in 82 patients with secondary RM are awaited with interest [21,22]. IVIg administration of Ig remains a feasible therapeutic option in patients with autoimmune disorders. The low rate of side effects, which improves quality of life, the possibility to withdraw the immunosuppressants and the steroidsparing effect make IVIg a viable option in selected patients with immune-mediated disorders when standard therapeutic regimens fail or when immunosuppressants are contraindicated.
Acknowledgements M. G. D. and Y. S. would like to thank Meridian HealthComms Ltd for providing medical writing services.
Disclosures M. G. D. has received an honorary fee from CSL Behring. Y. S. has received consulting support and grants from LFB and OMRIX.
References 1 Kwak JY, Kwak FM, Ainbinder SW, Ruiz AM, Beer AE. Elevated peripheral blood natural killer cells are effectively downregulated by immunoglobulin G infusion in women with recurrent spontaneous abortions. Am J Reprod Immunol 1996; 35:363–9. 2 Moraru M, Carbone J, Alecsandru D et al. Intravenous immunoglobulin treatment increased live birth rate in a Spanish cohort of women with recurrent reproductive failure and expanded CD56(+) cells. Am J Reprod Immunol 2012; 68:75–84. 3 Perricone R, Di Muzio G, Perricone C et al. High levels of peripheral blood NK cells in women suffering from recurrent spontaneous abortion are reverted from high-dose intravenous immunoglobulins. Am J Reprod Immunol 2006; 55:232–9. 4 Rigal D, Vermot-Desroches C, Heitz S, Bernaud J, Alfonsi F, Monier JC. Effects of intravenous immunoglobulins (IVIG) on peripheral blood B, NK, and T cell subpopulations in women with recurrent spontaneous abortions: specific effects on LFA-1 and CD56 molecules. Clin Immunol Immunopathol 1994; 71:309–14. 5 Roussev RG, Ng SC, Coulam CB. Natural killer cell functional activity suppression by intravenous immunoglobulin, intralipid and soluble human leukocyte antigen-G. Am J Reprod Immunol 2007; 57:262–9. 6 Ruiz JE, Kwak JY, Baum L et al. Intravenous immunoglobulin inhibits natural killer cell activity in vivo in women with recurrent spontaneous abortion. Am J Reprod Immunol 1996; 35:370–5. 7 Berman H, Rodríguez-Pintó I, Cervera R et al. Rituximab use in the catastrophic antiphospholipid syndrome: descriptive analysis of the CAPS registry patients receiving rituximab. Autoimmun Rev 2013; 12:1085–90. 8 Danieli MG, Gambini S, Pettinari L, Logullo F, Veronesi G, Gabrielli A. Impact of treatment on survival in polymyositis and dermatomyositis. A single-centre long-term follow-up study. Autoimmun Rev 2014; 13:1048–54. 9 Goebel A, Blaes F. Complex regional pain syndrome, prototype of a novel kind of autoimmune disease. Autoimmun Rev 2013; 12:682–6. 10 Lo E, Deane S. Diagnosis and classification of immune-mediated thrombocytopenia. Autoimmun Rev 2014; 13:577–83. 11 Rogosnitzky M, Danks R, Holt D. Intravenous immunoglobulin for the treatment of Crohn’s disease. Autoimmun Rev 2012; 12:275–80. 12 Ruffatti A, Marson P, Svaluto-Moreolo G et al. A combination therapy protocol of plasmapheresis, intravenous immunoglobulins and betamethasone to treat anti-Ro/La-related congenital atrioventricular block. A case series and review of the literature. Autoimmun Rev 2013; 12:768–73. 13 Saadoun D, Bodaghi B, Bienvenu B et al. Biotherapies in inflammatory ocular disorders: interferons, immunoglobulins, monoclonal antibodies. Autoimmun Rev 2013; 12:774–83. 14 Cousens LP, Tassone R, Mazer BD, Ramachandiran V, Scott DW, De Groot AS. Tregitope update: mechanism of action parallels IVIg. Autoimmun Rev 2013; 12:436–43. 15 Kaveri SV. Intravenous immunoglobulin: exploiting the potential of natural antibodies. Autoimmun Rev 2012; 11:792–4. 16 Danieli MG, Calcabrini L, Calabrese V, Marchetti A, Logullo F, Gabrielli A. Intravenous immunoglobulin as add on treatment with mycophenolate mofetil in severe myositis. Autoimmun Rev 2009; 9:124–7.
© 2014 British Society for Immunology, Clinical and Experimental Immunology, 178: 112–114
113
M. G. Danieli & Y. Shoenfeld 17 Gibofsky A. Epidemiology, pathophysiology, and diagnosis of rheumatoid arthritis: a synopsis. Am J Manag Care 2014; 20:s128– 45. 18 Atzeni F, Benucci M, Salli S, Bongiovanni S, Boccassini L, Sarzi-Puttini P. Different effects of biological drugs in rheumatoid arthritis. Autoimmun Rev 2013; 12:575–9. 19 Sticherling M, Erfurt-Berge C. Autoimmune blistering diseases of the skin. Autoimmun Rev 2012; 11:226–30. 20 Comarmond C, Cacoub P. Antiphospholipid syndrome: from pathogenesis to novel immunomodulatory therapies. Autoimmun Rev 2013; 12:752–7.
114
21 Clark DA. Intravenous immunoglobulin and idiopathic secondary recurrent miscarriage: methodological problems. Hum Reprod 2011; 26:2586–7; author reply 7–9. 22 Hutton B, Sharma R, Fergusson D et al. Use of intravenous immunoglobulin for treatment of recurrent miscarriage: a systematic review. Br J Obstet Gynaecol 2007; 114:134–42.
© 2014 British Society for Immunology, Clinical and Experimental Immunology, 178: 112–114
This document is a scanned copy of a printed document. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material.
