Clinical and Experimental Immunology



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


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.

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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.


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

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7th International Immunoglobulin Conference: Immunomodulation.

Immunomodulation uses synthetic, natural and recombinant preparations to modify the immune response to a desired level, typically to treat specific au...
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