• MYD88 protein
• MYD88 L265P mutation
• Waldenstrom’s macroglobulinemia
• monoclonal gammopathy of undetermined significance
• rituximab therapy

MYD88 protein is the canonical adapter for inflammatory signalling pathways to downstream members of the Toll-like receptor and interleukin-1 receptor families, leading to activation of the nuclear factor κB transcription factor. The MYD88 L265P mutation results in an aberrant activation of these pathways and it is specifically associated with clonal transformation of differentiating IgM B-cells, also through the expression of inflammatory cytokines. MYD88 L265P is considered a hallmark of Waldenstrom’s macroglobulinemia and B-cells lymphomas and may be helpful in the differential diagnosis from other lymphoproliferative neoplasms, such as multiple myeloma. Furthermore, it might represent an ideal marker for minimal residual disease monitoring and a specific status for development of new therapeutic approaches.
The importance to detect the mutational state of MYD88 in peripheral nerve disorders has been demonstrated by the evidence of high prevalence of the MYD88 L265P mutation in a cohort of patients with well-characterised polyneuropathy associated with anti-myelin associated glycoprotein (MAG) antibodies. This could have importance for a better clinical definition and therapeutic approach. The MYD88 L265P mutation could play a role in the immune-mediated attack on peripheral nerves conditioning clinical and electrophysiological heterogeneity of these neuropathies associated with the monoclonal IgM component, defining new therapeutic scenarios in this context.
The aim of the study was to identify a possible different phenotypic and electrophysiological expression of the disease in terms of severity and progression. In doing that, clinical, clinimetric and electrophysiological characterization of patients with myd88 mutation, respect to wild type patients at baseline and after rituximab therapy, in addition to serum inflammatory markers evaluation (IL1b, IL-6, IL-10, TNFa, INFb) was done. A group of CIDP patients was used as control group.
We have found that patients with myd-88 mutation had a distinct cytokine profile, with higher median IL-6 (p 0.00) and IL-10 (p 0.00) serum concentrations than IgM-np without mutation patients and CIDP patients. Furthermore, IL-10 concentration correlated directly with the MICARS scale scores (sig 0.003, r 0.529). Elevated IL-6 concentrations at baseline identified patients with a lower response to therapy in terms of disability (ONLS scores) at six months and elevated IL-10 concentrations directly correlated with an increase in the delta F ratio and therefore with a lower response to rituximab at six months (sig 0.048, r 0.365). Since follow-up in this study was relatively short, we cannot exclude the possibility that high concentrations of IL-10 and IL-6 require, in patients with myd88 mutation, a longer follow-up to show clear signs of clinical and electrophysiological recovery. However, IL-6 and IL-10 concentrations dropped significantly after 6 months of therapy, underlining how they may represent a monitoring parameter of rituximab therapy as occurs in routine practice with lymphocyte typing. Furthemore, after rituximab therapy, in myd-88 mutated patients significant improvements were recorded in the scores on the following clinical scales: DN4 (p 0.000), ONLS (p 0.014), mISS (p 0.000), FSS (p 0.000), MICARS part one (p 0.024).
Regarding electrophysiological data, myd-88 patients had a lower SNAP values in the upper limbs at onset, while motor nerves were relatively spared respect to patients without myd-88 mutation and mostly respect to CIDP patients. After therapy in Myd-88 patients there was a decrease in the latency of the motor response on the deep peroneal nerve and an improvement in the motor conduction on the deep peroneal and tibial nerves while, in the upper limbs, the terminal latency index was decreased. This trend cannot be confirmed for MUNE values: during the follow-up ABD MUNE loss continued and mean step area increased significantly.
Rituximab may represent an effective treatment for myd-88 mutation pnp. MUNE may be a suitable tool to quantify the pathological changes in motor units in myd-88 mutated patients, which role should be considered in the therapeutic follow-up of these patients.

In conclusion, myd-88 associated neuropathy have different and specific pathophysiological mechanisms respect to IgM neuropathy without mutation. It should be useful searching for the mutation to address specifically treatment strategies.