To describe the unique case of a patient with multiple sclerosis (MS) and anti–myelin-associated glycoprotein (MAG) polyneuropathy who developed MS relapses after treatment with rituximab.
Department of Neurosciences, Ophthalmology, and Genetics, University of Genova, Genova, Italy.
A 59-year-old man with an 18-year history of MS presented with an unusually rapid progression of paraparesis with hypopallesthesia and areflexia in 4 limbs. Neurophysiological and serological studies led to the diagnosis of anti-MAG polyneuropathy. Cerebrospinal fluid analysis disclosed the loss of oligoclonal IgG bands that were previously detected at MS onset.
Rituximab was administered at a dosage of 375 mg/m2/wk for 4 weeks.
The patient developed 2 corticosteroid-responsive MS relapses with improvement of the polyneuropathy.
Rituximab can be effective in anti-MAG polyneuropathy but can possibly lead to unexpected consequences in individuals with MS.
Rituximab is an anti-CD20 humanized antibody that depletes CD20+ B cells via antibody-dependent cytotoxicity and complement-dependent cytolysis. Data from our1 and other2 groups indicate that rituximab can be effective in anti–myelin-associated glycoprotein (MAG) polyneuropathy whereas discordant findings have been reported in multiple sclerosis (MS),3,4 a disease that could potentially benefit from the ability of the drug to decrease antibody production. We observed a dichotomous response to the drug in the herein-described patient after he developed anti-MAG polyneuropathy.
In a 59-year-old man, the clinical onset of MS occurred at age 41 years with hemifacial paresthesias that remitted after few months. One year later, the patient complained of fatigue and impotence. Neurological examination revealed spastic paraparesis in the lower limbs, brisk deep tendon reflexes, Babinski response, end-point rotatory nystagmus, and dysmetria in the right upper limb. Brain magnetic resonance imaging (MRI) showed focal high-signal-intensity lesions on T2-weighted images located in subcortical and periventricular areas, cerebellar peduncle, and midbrain. Visual and auditory evoked potentials were abnormal. Oligoclonal IgG bands (OCBs) were present in the cerebrospinal fluid, and therefore, a diagnosis of relapsing-remitting MS was made. Symptoms remitted after treatment with high doses of intravenous methylprednisolone, which was used also in the next documented 4 exacerbations. He did not receive any other immunosuppressive or immunomodulatory therapy. His clinical condition slowly deteriorated, and at the age of 51 years, he reached an Expanded Disability Status Scale (EDSS)5 score of 6 when in the secondary progressive phase of disease.
In April 2005, 18 years after MS onset, the patient's neurological condition rapidly deteriorated. Neurological examination confirmed a spastic paraparesis but disclosed previously unreported distal decreased vibratory and pinprick sensation and tendon areflexia in 4 limbs. Paresthesia was also present in the hands and feet. Neurophysiological studies showed a prevalently demyelinating sensory-motor polyneuropathy with extremely prolonged distal motor latencies and, in the peroneal nerve, a terminal latency index6 value of less than 0.25. Brain MRI confirmed the presence of multiple abnormalities in the periventricular white matter without enhancing lesions. These findings were not significantly different from those observed at the time of the previous MRI. Serum protein electrophoresis and subsequent immunofixation revealed a monoclonal IgM κ band. Free monoclonal κ light chains were detected in serum and urine. Serum immunoglobulin levels were, for IgG, 300 mg/dL (range, 800-1600 mg/dL); for IgM, 820 mg/dL (range, 40-230 mg/dL); and for IgA, 141 mg/dL (range, 70-400 mg/dL). Anti-MAG antibodies were detected in serum. Serum thyroid hormone levels, vitamin B12 levels, tumoral markers, hepatitis C serology, and blood glucose tests had normal or negative results. Results of bone marrow biopsy, thorax and abdomen computed tomography, and bone scintigraphy were compatible with a diagnosis of IgM monoclonal gammopathy of undetermined significance (MGUS). Cerebrospinal fluid examination unexpectedly did not show OCBs, which had been detected at time of MS diagnosis (image not available). However IgM/κ chain–specific staining confirmed the presence of an IgM κ monoclonal band in cerebrospinal fluid and serum (Figure). The patient, with a diagnosis of anti-MAG polyneuropathy and after signing informed consent, was treated with rituximab, 375 mg/m2/wk intravenous infusion, for 4 consecutive weeks.
Agarose isoelectric focusing and immunoblot of cerebrospinal fluid (CSF) and serum (Ser) samples taken before (Pre) and after (Post) rituximab treatment and stained for IgG or IgM/κ bands (arrow). Ctrl indicates the positive control for oligoclonal IgG bands.
Twelve-month follow-up consisted of clinical, electrophysiological, and immunological evaluations. Neurological assessment was performed at baseline and 1, 3, 6, and 12 months after the last rituximab infusion using the Medical Research Council (MRC) sumscore,7 Inflammatory Neuropathy Cause and Treatment (INCAT) Sensory Sumscore (ISS),8 and EDSS score. An improvement by 1 point in at least 2 scales was considered to be clinically relevant. At months 1 and 2, the patient had a sudden increase of motor weakness in his left limbs with spasticity and inability to walk. Accordingly, MRC and EDSS scores worsened at both points. Intravenous corticosteroids were followed by clinical improvement. Brain and cervical MRI did not show new lesions. Six months after rituximab treatment, a symmetrical sensorimotor improvement was registered in 4 limbs. In comparison with baseline values, the MRC sumscore (baseline, 40) improved by 3 points, ISS (baseline, 7) by 4 points, and EDSS (baseline, 6.5) by 0.5 points. The clinical course and the correlated scale scores remained stable up to month 12. Electrophysiological examinations were performed at baseline and 6 and 12 months after the treatment by measuring the parameters shown in the Table. A change of 10% or more in nerve conduction velocity was considered to be clinically relevant. All neurophysiological parameters in ulnar and median nerves improved with the exception of peroneal nerve motor conduction velocity. Sural nerve conduction velocity was not recordable. The most important immunohematological parameters were measured at each visit and included blood CD19+ B cells, which were undetectable after 1 month, reappeared at month 6, and returned to baseline values after 1 year, and anti-MAG–specific and total IgM (Table). At month 1 after rituximab treatment, cerebrospinal fluid analysis confirmed the absence of OCBs (Figure). Renal and liver functions were normal throughout follow-up.
A definite therapeutic spectrum has yet to be fully determined for rituximab. We used the drug in a unique context because the patient developed 2 diseases in which B-cell abnormalities are likely to play a putative pathogenetic role. Although we expected that rituximab could be beneficial in both the diseases, it improved the polyneuropathy but was followed by 2 MS relapses that occurred when the patient was in the secondary progressive phase of MS. We ascribed the deterioration in his condition to MS relapses because of (1) the sudden onset and the lateralization of symptoms, (2) the presence of spasticity, and (3) the prompt response to corticosteroids, to which anti-MAG neuropathy is unresponsive.9 Plausible causes for these post-rituximab relapses could only circumstantially refer to a B-cell depletion–related cyto-chemokinetic imbalance. However, the effects of the rituximab therapy were not invariably those we expected because in other settings, it only slightly reduced intravenous immunoglobulin dosage in a patient with intravenous immunoglobulin–dependent anti-MAG neuropathy10 or even worsened the disease.11 Overall, these findings suggest that therapeutic use of rituximab deserves further insight, notwithstanding its clear effect on B-cell depletion. We monitored this effect in our patient, who clinically improved after 6 months of treatment, with immunological tests. The test results paralleled the clinical improvement as well as those that studied electrophysiological aspects.
The occurrence of hematological disorders in non-immunosuppressed MS patients is very rare, and associations with MGUS have been only occasionally reported.12,13 These associations are too rare to support a causal link between the 2 diseases, although a pathogenetic role for persistent antigenic stimuli in yielding MGUS cannot be a priori excluded in a few MS cases. Chronic stimulation of immune system, which connotes MS,14 is indeed a risk factor for MGUS too.15 In MS, such stimulation probably underlies the presence of OCBs in cerebrospinal fluid. Surprisingly, and differently from what was reported in similar cases,12,13 our patient, who was OCB-positive at MS diagnosis, was found to be persistently OCB-negative after the onset of anti-MAG polyneuropathy and after rituximab treatment. This is a very unusual finding because OCBs represent a stable abnormality in MS,14 and they have only rarely been reported to transiently disappear only after intense immune suppression such as that from autologous hematopoietic stem cell transplantation.16 While B cells likely contribute to MS pathogenesis, the meaning of OCBs remains unknown.14 Cerebrospinal fluid findings in our patient, who experienced ongoing MS activity notwithstanding OCB disappearance, suggested that the monoclonal anti-MAG IgM could have primed mechanisms that interfere with persistent OCB production by oligoclonal plasma cells. Indeed, in patients with multiple myeloma/MGUS, it has been reported the existence of an autoimmune inhibitory network leading to the arrest in B-cell differentiation and consequent humoral immune deficiency,17 possibly sustaining, in this case, the disappearance of IgG OCBs. Such abnormality markedly affected the IgG isotype in our patient, in whom rituximab therapy, in turn, decreased anti-MAG–specific and total IgM levels.
In conclusion, this case confirms that rituximab represents a promising innovative approach in anti-MAG polyneuropathy, although it casts doubt on the use of rituximab in secondary progressive MS.
Correspondence: Luana Benedetti, MD, Department of Neurosciences, Ophthalmology, and Genetics, University of Genova, Via De Toni 5, 16132 Genova, Italy (email@example.com).
Accepted for Publication: March 8, 2007.
Author Contributions:Study concept and design: Benedetti and Franciotta. Acquisition of data: Benedetti, Vigo, Grandis, Fiorina, Ghiglione, and Roccatagliata. Analysis and interpretation of data: Benedetti, Mancardi, Uccelli, and Schenone. Drafting of the manuscript: Vigo, Grandis, Fiorina, Ghiglione, and Roccatagliata. Critical revision of the manuscript for important intellectual content: Benedetti, Franciotta, Mancardi, Uccelli, and Schenone. Administrative, technical, and material support: Vigo, Grandis, Fiorina, Ghiglione, and Roccatagliata. Study supervision: Benedetti, Franciotta, Mancardi, Uccelli, and Schenone.
Financial Disclosure: None reported.
Benedetti L, Franciotta D, Vigo T, Grandis M, Fiorina E, Ghiglione E, Roccatagliata L, Mancardi GL, Uccelli A, Schenone A. Relapses After Treatment With Rituximab in a Patient With Multiple Sclerosis and Anti–Myelin-Associated Glycoprotein Polyneuropathy. Arch Neurol. 2007;64(10):1531-1533. doi:10.1001/archneur.64.10.1531