Clinical and immunological worsening in a patient affected with Waldenstrom macroglobulinemia and anti-mag neuropathy after treatment with rituximab.

Current immune-modulating therapies for IgM paraproteinemic neuropathies (IgM-N) are often associated with severe complications and have not provided reliable evidences of long term efficacy. Neuropathy associated with antibodies to myelin-associated-glycoprotein (antiMAG) is a chronic-demyelinating sensorimotor neuropathy that counts for 50% of these diseases. Titre reduction of these antibodies has shown to be associated to an amelioration of the neuropathy. Therefore a selective drug address to reduce these antibodies is the target of current pharmacological researches. Rituximab is a mouse-human chimeric antibody directed against CD20 protein, eliminating the most of circulating Bcells. It has shown positive effects in the treatment of Bcell lymphoma, rheumatoid arthritis and preliminary studies suggested also a promising role in IgM-N. However, more recently several cases of clinical inefficacy or lack of effect on anti-MAG titre have been reported in patients treated with Rituximab, leading to unclear conclusions about the usefulness of this therapy. We reported the case of a 64-year-old-woman affected by Waldestrom macroglobulinemia and a neuropathy associated with anti-MAG IgM/k antibodies. The haematological disease was diagnosed by bone marrow biopsy, when the patient was 56-year-old. Neither multiorgan involvement, nor iperviscosity syndrome were associated and IgM-paraprotein level was stable for 8 years (from 4 to 5 gr/lt at periodical evaluations). At the age of 64, a severe tremor and unsteadiness of gait appeared. On neurological examination patient showed a mild increase of superficial, and a severe increase of propioceptive sensory threshold at lower limbs, apallestesia (loss of vibratory perception) from the knees, ataxic gait, positive Romberg sign, a 8 Hz-postural-kinetic tremor at all four limbs, areflexia, without any motor involvement. Neurophysiolgical studies included motor and sensory conduction velocities in two arm nerves and one leg nerve, F responses of the ulnar nerve and peroneal nerve, H reflex of the soleus muscle, and EMG of distal arm and leg muscles examinations disclosed a sensory-demyelinating polyneuropathy. Stimulated PBMCs were analyzed by flow-cytometry (Beckman-Coulter Inc.) to asses IL1β, IL2, IFNγ, TNFα, IL6, IL10, IL12 producing CD4+, CD8+ and CD14+ cell percentage (Caltag Lab). Quantitative immunoglobulins IgM in serum was determinated by rate nephelometry (Beckman Instruments) and anti MAG antibody titre was determined by electrophoresis(SEBIA ITALY) in serum. Serum anti-MAG IgM/k antibody titre and IgM level were 144.000 BTU and 5 gr/dL respectively; other antibodies to neuropathy-related-antigens as well as other toxic, metabolic, neoplastic, hereditary and infective causes of neuropathy were excluded. According to treatment recommendations in Waldestrom macroglobulinemia and previous reports, treatment with Rituximab was decide to be tempted. Rituximab was injected at a dosage of 375 mg/m once weekly for 4 weeks. As long as 3 months after theraphy, a severe worsening of all neurological signs and specifically of the tremor occured. Immunological-parameters assessed at pre-treatment (T0) and 3 months after therapy(T3) showed an increase of IgM levels and anti MAG titre, as reported in table 1 Rituximab treatment was stopped and after other six months, IgM levels went back to pre-treatment value (4,580 gr/lt) and anti-MAG antibodies decreased to 132.000 BTU, but the patient went on worsening. Flowcytometry was not re-assessed at that time. Rituximab is a monoclonal antibody that specifically binds CD20 antigen. Encouraging results about the usefulness of this drug in IgM-N come from open pilot Table 1A. The table shows (A) lymphocyte subsets (values are expressed as percentages % and as absolute cell number/ul ); (B) cytokines production by SEB + anti CD28 stimulated CD4, CD8, CD14 cells percentage; (C) IgM levels (gr/dl) measured by electrophoretic pattern and anti-MAG antibody titers measured by ELISA test. All immunological parameters have been analyzed before treatment (T0) and 3 months after therapy (T3). Statistically significant values are signed.