Luana Benedetti

Predictors of response to rituximab in patients with neuropathy and anti–myelin associated glycoprotein immunoglobulin M

Abstract  We evaluated the efficacy and safety of rituximab in an open‐label, uncontrolled study of 13 patients with polyneuropathy associated with antibodies to myelin‐associated glycoprotein (MAG) and correlated the response to therapy with clinical and laboratory features. One year after rituximab therapy, anti‐MAG immunoglobulin M (IgM) titers were significantly reduced. At that time, eight patients (62%) had improved in both the inflammatory neuropathy cause and treatment (INCAT) sensory sumscore and the Medical Research Council sumscore for muscle strength and seven of them also in the INCAT disability score. The improvement in the mean INCAT sensory sumscore was significant at 12 months and correlated with lower anti‐MAG antibody at entry and at follow‐up. This study suggests that rituximab may be efficacious in patients with anti–MAG associated neuropathy and particularly on sensory impairment and in those with moderately elevated antibody titers. These findings suggest that antibody reduction below a critical level may be necessary to achieve clinical improvement.

Rituximab in patients with chronic inflammatory demyelinating polyradiculoneuropathy: a report of 13 cases and review of the literature

Background A few case reports have shown controversial results of rituximab efficacy in patients with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). Objective To analyse the efficacy of rituximab in a large CIDP cohort. Methods A retrospective, observational and multicentre study on the use of rituximab in CIDP. 13 Italian CIDP patients were treated with rituximab after the partial or complete lack of efficacy of conventional therapies. Eight patients had co-occurring haematological diseases. Patients who improved by at least two points in standard clinical scales, or who reduced or discontinued the pre-rituximab therapies, were considered as responders. Results Nine patients (seven with haematological diseases) responded to rituximab: six of them, who were non-responders to conventional therapies, improved clinically, and the other three maintained the improvement that they usually achieved with intravenous immunoglobulin or plasma exchange. Significantly associated with shorter disease duration, rituximab responses started after a median period of 2.0 months (range, 1–6) and lasted for a median period of 1 year (range, 1–5). Conclusions Rituximab seems to be a promising therapeutic choice when it targets both CIDP and co-occurring haematological diseases. Timely post-onset administration of rituximab seems to be associated with better responses.

A nationwide retrospective analysis on the effect of immune therapies in patients with chronic inflammatory demyelinating polyradiculoneuropathy

Background and purpose:  The guidelines for chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) therapy suggest to use immunoglobulins (IVIg) and steroid as first‐line therapies. Patients who do not respond to one of the two drugs should be switched to the other drug. We collected therapeutic outcome data in patients followed at 11 centres in order to document the clinical practice in Italy.

LONG-TERM EFFECT OF RITUXIMAB IN ANTI-MAG POLYNEUROPATHY

Recent studies showed that rituximab, a chimeric anti-CD20 monoclonal antibody, reduces antibody levels and ameliorates neuropathy in two thirds of patients with neuropathy and anti-myelin-associated glycoprotein (MAG) monoclonal IgM.1–3 Few data are available on the long-term effects of this therapy.4 We report on the long-term follow-up of rituximab responders with anti-MAG polyneuropathy. ### Methods. Ten patients with anti-MAG polyneuropathy responding to rituximab, 375 mg/sq for four consecutive weekly infusions, were prospectively studied for 36 months. The effects of the initial treatment in 13 patients and the type of assessment were previously described.3 The baseline clinical and laboratory data of the 10 responding patients are reported in the table. All but one patient (no. 1) had an IgM monoclonal gammopathy of undetermined significance and a symptom duration of up to 2 years. Three patients had not been previously treated for the neuropathy, whereas seven were unresponsive to immune or cytostatic therapies. We considered as responders patients who improved at month 12 by at least one point in two clinical scales including MRC sumscore (appendix e-1 on the Neurology ® Web site at www.neurology.org), INCAT Disability Scale (appendix e-2), and INCAT sensory sumscore (ISS) …

Prevalence and characteristics of peripheral neuropathy in hepatitis C virus population

Objective: To assess the prevalence of peripheral neuropathy (PN) and its correlation with cryoglobulinemia (CG) in an unselected, untreated referral hepatitis C virus (HCV) population. Patients and Methods: Two hundred and thirty four patients (120 women and 114 men) with untreated HCV infection were consecutively enrolled by seven Italian centres. Clinical neuropathy was diagnosed when symptoms and signs of peripheral sensory or motor involvement were present. Median, ulnar, peroneal, and sural nerves were explored in all patients and distal symmetric polyneuropathy was diagnosed when all explored nerves or both lower limb nerves were affected. Mononeuropathy and mononeuropathy multiplex were diagnosed when one nerve or two non-contiguous nerves with asymmetrical distribution were affected. Screening for CG was done in 191 unselected patients. Results: Clinical signs of PN were observed in 25 of the 234 patients (10.6%). Electrophysiological PN was found in 36 (15.3%). CG was present in 56/191 patients (29.3%). The prevalence of CG increased significantly with age (p<0.001) and disease duration (p<0.05). PN was present in 12/56 (21%) patients with CG and 18/135 (13%) without CG (p = NS). PN increased significantly with age (p<0.001) and logistic regression analysis confirmed age as the only independent predictor of PN (OR 1.10 for each year; 95% CI 1.04 to 1.15; p<0.001). Conclusions: Electrophysiological examination detected subclinical neuropathy in 11 patients (4.7%). Statistical analysis showed that CG was not a risk factor for PN whereas PN prevalence increased significantly with age.

Immunosuppressive treatment in refractory chronic inflammatory demyelinating polyradiculoneuropathy. A nationwide retrospective analysis

Background and purpose:  There are other options open to patients with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) who are non‐responders to conventional treatment, including immunosuppressive and immunomodulatory agents (IA). The aim of this study was to assess whether the use of IA is able to increase the number of responders.

Mycophenolate mofetil in dysimmune neuropathies: A preliminary study

Mycophenolate mofetil (MM) is an immunosuppressant that has been used successfully for preventing the rejection of renal, heart, or liver transplants and for the therapy of immune-mediated diseases.4 It shows modest side effects and has a lower risk for late malignancies compared with other immunosuppressive drugs.1 Recently, MM has been used also for the treatment of myasthenia gravis, polymyositis, chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), and multifocal motor neuropathy (MMN).2,7,10 We treated four patients with possible, probable, or definite MMN11 and two with CIDP8 (Table 1) who were on large doses of intravenous immunoglobulins (IVIg), with the hope of reducing or withdrawing IVIg while maintaining a satisfactory and stable clinical state. Four patients were also receiving other immunomodulating agents. Patients received oral MM in a dosage of 1 g twice daily, for an average of 9 months (range, 6–12 months). Prior to MM treatment, all patients underwent several attempts to reduce IVIg dosage, resulting in clinical worsening, even in subjects receiving other immunomodulating agents. Patients were evaluated at baseline and each month thereafter, using the Medical Research Council (MRC) sumscore6 and the Immune Neuropathy Course and Treatment (INCAT) arm and leg disability scores.5 The values of the INCAT scale at baseline ranged from 0 to 3 (mean, 1.5). Full blood count, renal and liver function, and serum amylase levels were monitored every 2 months. Side effects were recorded and graded according to the Common Terminology Criteria for Adverse Events.9 All the patients provided informed consent to participate in the study. Table 1 summarizes the details of each patient. In five patients we did not observe any worsening in MRC sumscore or INCAT disability scale despite a significant reduction in IVIg dosage. On average, before starting MM treatment patients received 2g/kg every 4 weeks. After 6 months the mean dosage of IVIg was 0.75 g/kg every 4 weeks. In patients 1 and 2, IVIg infusion was reduced by 50% after 2 months and discontinued after 4 months. After 1 year of therapy with MM, IVIg treatment remains discontinued. In patient 4, the addition of MM allowed a reduction in IVIg dose to 50% after 4 months. In patient 3, IVIg dose was reduced by 25% but only for 4 months; symptoms relapse then required a return to the previous IVIg schedule. In patients 5 and 6, who had CIDP, IVIg dosage was reduced by 50%. After follow-up ranging from 6 to 12 months there was no deterioration in the MRC sumscore or in the INCAT disability scale in patients 1, 2, 4, 5, and 6; indeed, in patients 1 and 2 we observed a minimal improvement of overall disability within 2 months of starting MM. Finally, azathioprine (patients 3, 5, and 6) and cyclophosphamide (patient 2) were discontinued after 3 months of combined IVIg and MM treatment. Patients 1 and 4 discontinued MM because of loss of appetite, weight loss, abdominal pain, and increase of amylase levels (grade 1 in both cases). Patient 5 developed mild leukopenia (grade 1). Recently, MM has been introduced for the treatment of immune-mediated neuromuscular disorders,2,3 but the findings in only one patient with MMN and nine patients with CIDP have been published, to our knowledge, with conflicting results.7,10 We found that MM, in patients with MMN and CIDP, is effective in reducing IVIg requirement and in replacing other, more toxic, drugs. Only one patient with MMN relapsed, after 4 months, perhaps because of longer duration of disease, as previously observed in another series of patients.10 In fact, axonal impairment, more than immune-mediated de-

Validation of the Italian version of the Neuropathic Pain Symptom Inventory in peripheral nervous system diseases

The aim of this study was to validate the Italian version of the Neuropathic Pain Symptom Inventory (NPSI) in patients with neuropathic pain due to peripheral nerve diseases, and also to evaluate the validity of a new NPSI score: a frequency weighted NPSI score (NPSI-FW). First, the original version of the NPSI was translated into Italian. Then the validity and reliability of the Italian NPSI (I-NPSI) were tested in 392 Italian patients consecutively referred to 16 Italian outpatient services for peripheral nerve diseases, by correlating the I-NPSI scores with other pain scales. The repeatability and responsiveness were assessed. A significant correlation between the I-NPSI scores and all the other pain measures was seen. Reproducibility and responsiveness were good. Our study shows the validity of the I-NPSI and demonstrates its reliability for assessing neuropathic pain in patients with peripheral nerve diseases. The I-NPSI scores represent reliable measurements to assess neuropathic symptoms and effectiveness of treatment on them.

Impairment of PMP22 transgenic Schwann cells differentiation in culture: implications for Charcot-Marie-Tooth type 1A disease

Charcot-Marie-Tooth type 1A (CMT1A) is a hereditary demyelinating neuropathy due to an increased genetic dosage of the peripheral myelin protein 22 (PMP22). The mechanisms leading from PMP22 overexpression to impairment of myelination are still unclear. We evaluated expression and processing of PMP22, viability, proliferation, migration, motility and shaping properties, and ability of forming myelin of PMP22 transgenic (PMP22(tg)) Schwann cells in culture. In basal conditions, PMP22(tg) Schwann cells, although expressing higher PMP22 levels than control ones, show normal motility, migration and shaping properties. Addition of forskolin to the media induces an additional stimulation of PMP22 expression and results in an impairment of cells migration and motility, and a reduction of cell area and perimeter. Similarly, co-culturing transgenic Schwann cells with neurons causes an altered cells differentiation and an impairment of myelin formation. In conclusion, exposure of PMP22(tg) Schwann to the axon or to axonal-mimicking stimuli significantly affects the transition of transgenic Schwann cells to the myelinating phenotype.

RITUXIMAB EFFICACY IN CIDP ASSOCIATED WITH IDIOPATHIC THROMBOCYTOPENIC PURPURA

Devised for the treatment of B-cell lymphoproliferative disorders, the anti-CD20 antibody rituximab is now used for many B-cell–mediated diseases. We describe a patient whose co-occurring chronic inflammatory demyelinating polyneuropathy (CIDP) and idiopathic thrombocytopenic purpura (ITP) were refractory to conventional therapies but responsive to rituximab. In January 2005, a 58-year-old man complained of hand and foot paresthesias. Sensory symptoms progressed to both knees, fatigue began to affect both legs, and he began walking with crutches 4 months from onset. Neurological examination showed loss of strength, decreased vibratory-pinprick sensation, and tendon areflexia in all four limbs. Neurophysiological studies showed reduced motor nerve conduction velocity with conduction blocks in left peroneal and ulnar nerves (Table 1). A sural sensory nerve action potential was not recordable. Cerebrospinal fluid examination revealed normal cell count, elevated proteins, and identical cerebrospinal fluid and serum oligoclonal bands. Serum tumor markers, thyroid hormones, vitamin B12, glucose, and anti–myelin-associated glycoprotein (anti-MAG)/ganglioside antibodies were normal. Hematologic analysis showed mild thrombocytopenia (Table 1). After a diagnosis of CIDP was made, the patient was treated with intravenous immunoglobulin (IVIg; 0.4 g/kg/day for 5 days). Symptoms and signs improved, and the patient was able to walk without crutches. In June 2005, a CIDP relapse manifested in the form of loss of hand and foot strength, and of dysphagia. Platelet count decreased markedly (Table 1), without purpura. Bone marrow biopsy disclosed normal megakaryocyte count without dysplasia. Serological tests for ANA antinuclear antibodies, ENA extractable nuclear antigen antibodies, ACA anti-cardiolipin antibodies, ANCA anti-neutrophil cytoplasmic antibodies, HIV-1/2 human immunodeficiency virus, CMV cytomegalovirus, HBV hepatitis B virus, HCV hepatitis C virus, EBV Epstein-Barr virus, and HSV-1/2 herpes simplex virus were negative. ITP was diagnosed. The CIDP relapse was treated with a second course of IVIg (0.4 g/kg/day for 5 days) plus oral prednisone (1 mg/kg/day). Neurological symptoms improved briefly, but thrombocytopenia persisted. Two further relapses occurred in 5 months, and both were treated with the previously used IVIg plus prednisone schedule. Clinical improvement was transient, and thrombocytopenia was unchanged. Splenectomy was suggested for ITP. Because we felt that plasma exchange would not be more effective than IVIg in sustaining long-lasting clinical benefit, and neither able to prevent splenectomy, we elected to treat the patient with rituximab, 375 mg/m/ week, infused intravenously, for 4 consecutive weeks. This therapy started after the last IVIg cycle, which had briefly improved neurological symptoms. Prednisone, which had been administered for 6 months, was gradually tapered off. Table 1 shows 18-month follow-up data. At this follow-up: (a) CIDP relapse did not occur, and IVIg treatment was not required; (b) neurological sequelae and motor conduction velocity (overall in ulnar nerve) improved; (c) conduction blocks disappeared; (d) platelet counts were almost normal; and (e) blood CD19 B cells, initially undetectable, returned to baseline. Our CIDP–ITP patient improved after rituximab therapy, without the complication of infections. Rituximab