Johannes P. M. van de Mortel

Polyneuropathy associated with an immunoglobulin M (IgM) monoclonal gammopathy is characterized by slowly progressive, predominantly distal sensorimotor deficits, sensory ataxia, and electrophysiologic features of demyelination. IgM antibodies against myelin-associated glycoprotein (MAG) are present in serum from most patients. Nerve damage most likely results from the concerted action of binding of anti-MAG antibodies to nerves, followed by complement activation. The interaction of anti-MAG antibodies with complement activation and their relation to clinical characteristics have not been studied in detail. We studied the correlation among anti-MAG antibody titers, complement activation, and IgM-associated polyneuropathy disease severity. We used serum samples from 101 patients with IgM-associated polyneuropathy to assess IgM anti-MAG titers by ELISA and antibody-mediated complement deposition using both an ELISA-based system and a cell-based system of primate peripheral nerve slides. We studied correlations of complement activation with anti-MAG ELISA titers and clinical characteristics. IgM anti-MAG titers varied from negative to strongly positive. Complement deposition in the ELISA-based system correlated significantly with anti-MAG antibody titer (Spearman rho 0.80; p < 0.0001) despite large variability between serum samples with comparable anti-MAG titers. This variability was even larger in the cell-based assay, which also showed complement deposition in IgM anti-MAG negative patients, indicating the presence of autoantibodies directed against epitopes other than MAG in a subset of patients with IgM-associated polyneuropathy. Clinical characteristics did not correlate with anti-MAG titers or complement activation. Anti-MAG antibody titers correlate with the level of complement activation in both ELISA and cell-based systems. However, clinical characteristics of IgM-associated polyneuropathy do not or only weakly correlate with titers or the level of complement deposition. The lack of clear correlations between complement activation and clinical characteristics does, at this stage, not support the use of complement inhibitors in the treatment of IgM-associated polyneuropathy.

With increasing age, the chances of developing either MGUS or polyneuropathy increase as well. In some cases, there is a causative relationship between the IgM M-protein and polyneuropathy. In approximately half of these cases, IgM targets the myelin-associated glycoprotein (MAG). This results in chronic polyneuropathy with slowly progressive, predominantly sensory neurological deficits and distally demyelinating features in nerve conduction studies. Despite the disease being chronic and developing slowly, it can cause considerable impairment. We reviewed English medical publications between 1980 and May 2022 on IgM gammopathy-associated polyneuropathy, with special attention to studies addressing the pathophysiology or treatment of anti-MAG polyneuropathy. Treatment options have been limited to a temporizing effect of intravenous immunoglobulins in some patients and a more sustained effect of rituximab but in only 30 to 55 percent of patients. An increase in our knowledge concerning genetic mutations, particularly the MYD88^L265P mutation, led to the development of novel targeted treatment options such as BTK inhibitors. Similarly, due to the increasing knowledge of the pathophysiology of anti-MAG polyneuropathy, new treatment options are emerging. Since anti-MAG polyneuropathy is a rare disease with diverse symptomatology, large trials with good outcome measures are a challenge.