This study demonstrates that reduction of IgG levels by targeting the FcRn recycling system does not mitigate peripheral nerve inflammation in ICAM1-deficient NOD mice—an animal model for chronic neuritis.

Targeting the FcRn mechanism has been established as a new therapeutic approach for the treatment of IgG-mediated autoimmune diseases. Clinical trials to study FcRn blockade have been initiated for various conditions such as immune thrombocytopenia (ITP-phase 2 trial) [10, 11], generalised myasthenia gravis (MG-phase 2 trials [12, 13], MG-phase 3 trials [14, 15]) and CIDP. In immune-mediated neuropathies, FcRn modulation is a promising candidate and potential alternative to IVIg, corticosteroids or apheresis therapy.

It is anticipated that FcRn blockade might be beneficial for a subgroup of CIDP patients, targeting pathophysiologically relevant IgGs and enabling a more individually tailored treatment strategy. A recent study in CIDP patients tested an FcRn monoclonal antibody, (IgG4P) rozanolixizumab, which led to > 80% reduction of IgG but failed to meet the primary endpoint, which was changed from baseline to week 13 in inflammatory Rasch-built Overall Disability Scale (iRODS) score [16]. Comparison of treatment efficacy was complicated because almost two-thirds of patients in the placebo arm remained stable, possibly due to the study design, which only included patients with historic IVIg dependency. It is hoped that ongoing, well-designed clinical trials in CIDP patients may provide further insights on the potential for FcRn modulating agents in this complex condition. Ongoing phase 2 trials in patients with CIDP with batoclimab (NCT05581199) and nipocalimab (NCT05327114)—agents targeting the FcRn system—will explore the value of this therapeutic approach. Recently, a clinical trial treating patients with CIDP with efgartigimod (ADHERE + ; NCT04280718) showed promising efficacy.

Based on these results, the FDA most recently approved efgartigimod as a new treatment for patients with CIDP. The therapeutic approach does work, at least in a subset of CIDP patients since the study analysed a highly enriched cohort of CIDP patients in terms of stratification. However, in the best-case scenario, the efficacy of efgartigimod addressing the FcRn system may be partially based on complementary mechanisms beyond autoantibody reduction, such as modulation of macrophages.

In our animal study, an anti-mouse monoclonal FcRn antibody of the IgG1 isotype has been employed, and treatment resulted in a reduction of serum IgG levels of 65%, while IgM levels were not affected. Conceivably, this IgG reduction may not have been strong enough to induce a clinical treatment effect in these NOD-ICAM1-deficient mice. Moreover, the importance of B cells and the humoral immune system in the NOD-ICAM-deficient mouse model is still a matter of debate. Despite the fact that adoptive transfer of T cells can induce the disease, the humoral immune system also seems to be involved in its pathophysiology since nerve infiltrates do not only comprise T cells but also contain high numbers of B cells [8]. Indeed, in single-cell transcriptomics of the NOD-ICAM1-deficient mouse, nerve infiltrates contained B cells with an activated phenotype [17]. The serum of affected animals reacts with different components of the PNS, indicating the presence of self-reacting antibodies in the NOD-ICAM-deficient mouse model [8]. Nevertheless, the destructive capacity of these autoantibodies is still not proven, and it is not clear to what extent they result in disease. Our data indicate that reduction of IgG might not ameliorate autoimmune neuritis in the NOD-ICAM1-deficient mouse. Rather, the data suggest that the therapeutic effect of hipIg—at least in the neuritis mouse model—is independent on IgG levels, pleiotropic and not only driven by their ability to reduce IgG recycling by FcRn saturation. This may also be relevant for a subgroup of patients with CIDP. Here, it has been speculated that the initial immune response is T cell driven, while chronic disease phase is underpinned by predominantly humoral responses [18]. Ongoing inflammatory responses could induce the process of epitope spreading, thereby broadening the antigenic repertoire, leading to a secondary relevance of autoantibodies. Although T cell proliferation [19] and increased numbers of CD4+ T cells and CD8+ T cells featuring oligoclonal expansions in patients with CIDP [20, 21] underline the importance of cytotoxic T cells in the pathogenesis of CIDP [20, 21], antibodies against structures of the peripheral nervous system have been recently described [22]. These findings may define new subtypes of immune-mediated neuropathies and further emphasise the role of the humoral immune response in CIDP in the coming years.

The broad efficacy of IVIg in the treatment of CIDP is rooted in the ability to exert a number of different mechanisms of action [4] such as the reduction in oligoclonal T cell expansion, particularly within the CD8+ T cell population [20]. IVIg treatment is also associated with an alteration of regulatory NK cell numbers [23] in CIDP patients. Since a proportion of patients do not respond to IVIg, corticosteroids or apheresis therapy, and IVIg availability remains a problem, there is an unmet need to broaden the therapeutic armamentarium in immune-mediated neuropathies. FcRn blockade might be a suitable option for a group of CIDP patients, targeting pathophysiologically relevant IgGs and enabling more individually tailored treatment strategies.