Immunoglobulins: current understanding and future directions

The 7^th International Immunoglobulin Conference covered diverse topics related to immunoglobulins (Ig), both at the molecular and clinical levels. The presentations and insightful discussions featured original uses of IgG therapy based on new clinical experience and research across specialities, including immunology, neurology, transplantation, dermatology and rheumatology. The aim of the conference was to gain a better understanding of the biology and clinical mechanism of action of therapeutic Ig, to stimulate change in medical practice and improve patient care.

Immunodeficiencies

Although IgG is a well-established replacement therapy for primary immunodeficiencies (PID), a number of challenges remain when considering the optimal treatment regimen. Immunodeficiencies such as common variable immunodeficiency (CVID) present with complex and diverse phenotypes and a wide range of underlying genetic causes 1. Meta- and other statistical analyses of clinical trials in PID patients have demonstrated that the IgG trough level is associated with the occurrence of lung or overall infection 2,3. However, the IgG trough levels required to prevent breakthrough bacterial infections varies between patients, indicating a need for individual dosing to maintain a patient free from infection 4–6. The issue of end-of-cycle loss of efficacy (wear-off) may result in a higher frequency of infection at the end of a dosing cycle 7, and may affect the accurate determination of an optimal IgG dose; however, the use of subcutaneous rather than intravenous immunoglobulin (SCIg and IVIg, respectively) administration may minimize wear-off 8. Guidance is available to assist with dosage and treatment interval when switching from IVIg to SCIg 9,10; a simulation has also been developed to aid SCIg dosing in newly diagnosed PID patients 11 and the therapeutic options summarized in a recent review 12.

Both IVIg and SCIg have been shown to be effective when administered by these routes, although data from the European Society of Immunodeficiencies (ESID) registry has shown that clinical outcomes vary markedly, with patients receiving IVIg appearing to present with more infections and spend more days in hospital, although the interpretation of this finding remains complex 13. SCIg administration also reduces variation in peak and trough serum IgG levels compared with IVIg 8, as smaller volumes were administered with SCIg leading to shorter treatment intervals. Facilitated infusion of SCIg, for example by carrying out pre-infusion with recombinant human hyaluronidase, permits a SCIg administration at a single site with an infusion rate and interval more comparable to that of IVIg 14.

Interestingly, a retrospective study of 23 PID patients indicated that alternating IVIg and SCIg therapy as the patient's requirements and circumstances change is convenient for the patient while maintaining efficacy and safety 15. Additionally, a recent patient survey highlighted the importance of providing access to different treatment options and modes of administration to meet patient needs and to improve health-related quality of life 16. The survey was carried out across 300 PID patients in 21 countries, and although the majority of patients expressed satisfaction with their current treatment, there were clear preferences for self-administration at home and for shorter treatment duration. However, it is important to note that while physicians may wish to offer patients the choice of therapy, it is not always possible. Data presented from the ESID Primary Immunodeficiencies Care in Development Working Party (PIDCD WP) demonstrate that although IVIg is available in all European countries, access to SCIg varies between countries and not all are able to comply with recommended dosing protocols (usually for economic reasons). Moreover, as demand for Ig treatment increases, it is vital to consider how best to apply limited resources, and algorithms have been suggested to prioritize indications and ensure that therapy reaches those patients who most need it 17.

As well as optimizing treatment, accurate and early diagnosis of PID is essential to prevent long-term organ damage and infections. Thus it was exciting to learn of progress in an ongoing pilot study to evaluate neonates for severe B cell as well as T cell PID. The technique under evaluation uses a combination of the signal joint T cell receptor excision circles (TRECs) and B cell κ-deleting excision circles (KRECs) analysis into a triplex polymerase chain reaction (PCR) method, which has been shown to be effective in identifying patients with severe combined immunodeficiencies and X-linked agammaglobulinaemia 18. The substantive growth of patient registries, with more than 25 000 patients included in the ESID and Latin American Society for Immunodeficiencies (LASID) registries, offers promise of future insights into diagnosis and treatment, as well as epidemiological and other factors influencing clinical course. It was inspiring to hear the call to forget about politics and focus instead on registering patients, improving the knowledge base available for all.

Autoimmune diseases

In addition to PID and secondary immunodeficiencies, IgG therapy is an important treatment for indications which rely more heavily upon the immunomodulatory effects of IVIg. High-dose IVIg is being increasingly utilized as an off-label therapy for autoimmune bullous dermatoses, with studies demonstrating a significant reduction in pathogenic autoantibodies 19,20. The results of a recent randomized trial in seven patients with very severe pemphigus were presented, indicating a greater reduction in pathogenic autoantibodies when IVIg was used in combination with cyclophosphamide than IVIg alone. Preliminary results presented at this conference from a recently completed randomized controlled trial in 82 patients with secondary recurrent miscarriage (RM) and a meta-analysis of studies evaluating IVIg in RM suggested that IVIg may be beneficial in this disorder; more data will be available soon to support these encouraging results. Additionally, promising new findings in rheumatoid arthritis (RA) add to older data to support some limited application of IVIg in this condition.

Neurological disorders

Ig therapy is an established first- and second-line treatment option for immune-mediated peripheral neuropathies. Evaluation of both IVIg and SCIg has confirmed that these treatments are safe and well tolerated in chronic inflammatory demyelinating polyneuropathy (CIDP) and multifocal motor neuropathy (MMN) 21–24. Long-term use of IVIg in CIDP reduces the autoreactive T cell response, and the assessment of this response is suggested as a biomarker to predict responsiveness to IVIg 25. The benefits of various add-on therapies in combination with IVIg, such as corticosteroids, plasmapheresis or immunosuppressants, were reviewed in Guillain-Barré syndrome (GBS), MMN and CIDP. In general, add-on therapies were not shown to have an additional beneficial effect compared with IVIg alone. Corticosteroids and plasmapheresis in patients with MMN may worsen the condition 26.

There has been a great deal of anticipation regarding the use of IVIg in Alzheimer's disease (AD), as well as some trepidation concerning the prioritization of limited Ig resources. However, the Phase III clinical trial of IVIg in AD failed to meet its primary outcome objectives 27. In post-hoc analyses, some small benefits were observed in patients carrying the APOE-e4 allele and those with moderate-stage disease, indicating that IVIg may be of use in a subgroup of AD patients with specific genetic or biological markers. However, further confirmation is needed.

New areas of research for the use of IVIg include antibody-mediated central nervous system (CNS) diseases, such as autoimmune encephalitis, and chronic pain, although the mechanisms that initiate and maintain the autoimmune responses in these indications remain unclear. In anti-N-methyl-_D-aspartate (NMDA) receptor encephalitis, first-line immunotherapy including IVIg and corticosteroids resulted in approximately 50% of patients showing a response within 4 weeks 28. In a randomized controlled trial with IVIg to treat chronic pain in 12 complex regional pain syndrome (CRPS) patients, 25% of subjects experienced >50% of pain relief after IVIg treatment 29. More recently, evidence supporting the use of IgG in a range of chronic pain conditions was presented at an expert workshop held in 2012 30, indicating that autoantibody-mediated autoimmunity may be a relevant pathomechanism in these disorders. Randomized controlled trials are currently ongoing in order to investigate IgG further as a treatment in chronic pain conditions.

As already shown to be of value in PID, there is a movement towards individualized therapy when administering IgG to treat neuropathies, and this is supported by the European Federation of Neurological Societies/Peripheral Nerve Society (EFNS/PNS) guidelines 31. The current dosing recommendations for neurological disorders have been extrapolated from earlier studies in idiopathic thrombocytopenic purpura/immune thrombocytopenia (ITP) with small numbers of patients, while actual current clinical practice uses a broad range of dosages 32. As with PID, a wear-off effect has been observed with IVIg in neuropathies and the individualized maintenance of stable serum IgG levels is thought to be required in order to avoid wear-off effects for patients 33,34. Increasing the frequency of dosing to achieve consistent serum IgG levels, possibly by initiating SCIg therapy, may help to achieve this.

Transplantation

For the first time, the scientific programme included a plenary session on transplantation, which covered a variety of topics relating to allograft survival and function. Allograft rejection remains the chief obstacle to transplant success, in particular for those patients with elevated donor-specific anti-human leucocyte antigen (HLA) antibodies (DSA). DSA have been shown to promote antibody-mediated rejection (AMR) through activation of the complement cascade, and assessment of the complement-binding capacity of DSA can be used to identify patients at high risk of allograft rejection 35. However, the clinical significance of antibodies detected by high-sensitivity techniques, such as solid-phase immunoassay, is not yet understood 36. Early detection of DSA allows risk stratification of transplant recipients and thus may impact upon long-term allograft survival. IVIg therapy in combination with plasma exchange and/or rituximab offers the potential to desensitize renal transplant patients with DSA and improve survival 37,38. This combined treatment strategy improves cost-effectiveness when compared with a regimen relying on dialysis.

A further step forward was the identification of various phenotypes of AMR by histological characteristics, including subclinical 39, C4d-negative 40, AMR with vascular lesions 40 and AMR without anti-HLA antibodies but with DSA of other origin 41. These phenotypes vary in severity, and targeting therapeutic interventions to these phenotypes may lead to improved patient outcomes. Subpopulations of B cells may also act as immunoregulatory cells, and although B cells may play a role in acute cellular rejection there is mounting evidence that they may also be beneficial for long-term graft survival 42,43, possibly by promotion of regulatory T cell development via transforming growth factor (TGF)-β production 44. Thus, modulation of B cells may be a worthwhile target for novel therapeutic strategies.

Finally, a meta-analysis of 1756 patients across 18 studies found that hypogammaglobulinaemia following transplantation was associated with increased risk of infection and higher mortality; surprisingly however, the incidence of hypogammaglobulinaemia had no effect on transplant rejection 45. Treatment of hypogammaglobulinaemia with IVIg reduced the overall rate of infection 46–50 and, despite the finding that hypogammaglobulinaemia did not affect transplant rejection, some studies observed reduced graft rejection in heart transplant patients treated with IVIg 48,49.

Mechanisms of action

Understanding the mechanism of action of Ig therapy in immune-mediated disorders is invaluable in order to guide rational treatment, and the mechanism of action may vary in different disorders. The immunomodulatory effect of Ig administration depends on multiple mechanisms, including binding of the Fc-fragment of IgG to Fc-gamma receptors (FcγRs) on target cells, and Fc-independent mechanisms such as binding of the Fab variable region of IgG to foreign antigens, self-antigens and anti-idiotypic antibodies. There is evidence that sialylation of both the Fc and Fab regions of IgG may be involved in mediating the anti-inflammatory action of IVIg; however, conflicting evidence in models of ITP and RA suggested that further research is required to clarify the role of IgG sialylation in these disorders 51–53. Results from 174 GBS patients suggest that treatment with IVIg results in increased serum IgG galactosylation and, to a lesser extent, sialylation, and this is associated with improved clinical recovery 54. Genetic variation in both the FcγRs and the neonatal Fc receptor (FcRn) are associated with both the incidence of autoimmune diseases and the efficacy of IVIg treatment 55–58. Results were also presented that demonstrate that IVIg/SCIg preparations contain a range of anti-carbohydrate IgG antibodies to glycan-host attachment sites for pathogens, which could potentially be exploited for the design of potent glycovaccines. In addition to these mechanisms, a recent study has concluded that high-dose IVIg treatment inhibits the inflammatory response of circulating myeloid dendritic cells by down-regulating expression of FcγRIIa and interferon (IFN)-γR2 59. No up-regulation of FcγRIIb was observed, and the authors suggest that this expression cascade is initiated by stimulation of interleukin (IL)-33 production via dendritic cell-specific intercellular adhesion molecule-3 (ICAM-3) grabbing non-integrin receptor (DC-SIGN)-independent mechanisms. Immunoglobulins other than IgG may also be involved in the mechanism of action of Ig administration. For example, IgA can act via the SIGNR1 receptor or the IgA Fc receptor to suppress immune responses and act as an immunomodulator in inflammatory diseases 60,61. Additionally, breakthrough bronchitis and sinusitis infections in PID patients treated with IVIg may be related to reduced levels of IgA and IgM 62.

Adverse events

There have been concerns regarding adverse effects associated with Ig therapy, including thrombosis and haemolysis. An extensive literature review presented at this conference suggests that IVIg-related thromboembolic events are rare, and noted that IVIg treatment in animal models that mimic thrombogenic conditions appears, in contrast, to be beneficial 63,64. Additionally, when comparing the incidence of stroke among PID patients receiving IVIg from the United States Immunodeficiency Network (USIDNET) registry with the incidence in the general population of the United States 65, IVIg appears to have a protective effect, particularly in patients aged more than 65 years. In a review of the haemolytic events reported to vigilance groups as associated with Ig infusions between 1998 and 2012 in North America and Europe, 925 cases were documented and 34 related deaths reported 66. While the fatality rate of 2·4 deaths/year is low, steps are currently under way to reduce the titre of isoagglutinins in Ig preparations. It thus appears that thrombosis and haemolysis events following Ig therapy cannot be limited to a single cause-and-effect, and further studies are required to investigate, and potentially act upon, these phenomena.

A look to the future

There have been many exciting innovations since the last International Immunoglobulin Conference, and we can expect further developments in the field of Ig therapy in the years ahead. Treatment individualization is becoming a major focus in all fields, and we predict advances in the optimization of treatment with more concentrated Ig infusions and additional administration regimens that offer increased flexibility. Greater understanding of the underlying mechanisms of Ig therapy will assist in achieving optimal patient outcomes by helping physicians to recognize when Ig dosing is sufficient, why it works and which patients will respond. Ig therapy is used in a wide range of indications, including primary immunodeficiency, transplantation and various neurological, rheumatological, dermatological and reproductive immunological disorders, with particular growth expected in secondary immunodeficiencies and immunoregulatory applications. Although there are emerging indications which will result in the increased use of IgG this may be balanced, to some extent, by a decline in IgG use in other conditions where biological therapies may also be effective.

Future applications may come from a growing understanding of the role of FcRn in the recycling of IgG, and recognition that IgG levels in humans are more dependent on recycling than on the production of new Ig 67. There is already an emerging pipeline of agents that target FcRn to reduce IgG recycling in autoimmune disease.

The roles of IgA and IgM are also undergoing re-evaluation. The importance of IgA in immune exclusion (the inhibition of adherence of noxious microorganisms and antigens to the epithelium by secretory Ig) 68, anti-inflammation and maintenance and homeostasis of commensals and the microbiome is becoming more clear. IgM has a number of functions related to elimination of infection, B cell homeostasis, the removal of apoptotic cells, modulation of inflammation, autoimmunity and atherosclerosis. Furthermore, IgM is reduced following B cell ablation therapies. These findings may lead us to reconsider the extraction of IgA and IgM from plasma during the manufacturing process with a view to potential therapies for clinical states of immune dysfunction and deficiency.

We have come a long way in our understanding of Ig and its therapeutic applications. Nevertheless, the presentations at the 7^th International Immunoglobulin Conference have illustrated how much more there is to discover. We look forward to engaging in further basic and clinical studies to address the gaps in our knowledge at future expert meetings on the topic of therapeutic applications of Ig.

Disclosures

S. J. has received support for consulting, conferences and/or research from CSL Behring, Baxter, BPL, Biotest, Octapharma, Shire and SOBI. S. C. J. has received research grant support and consulting support from CSL Behring. J. S. O. has received consulting honoraria from CSL Behring, Baxter, ASD and Atlantic Research Group, and a research grant from CSL Behring. I. N. v. S. received departmental honoraria for serving on scientific advisory boards and a steering committee for CSL Behring.