Rituximab in patients with chronic inflammatory demyelinating polyradiculoneuropathy: a report of 13 cases and review of the literature.
ABSTRACT A few case reports have shown controversial results of rituximab efficacy in patients with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP).
To analyse the efficacy of rituximab in a large CIDP cohort.
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.
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).
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.
- [Show abstract] [Hide abstract]
ABSTRACT: La polyradiculoneuropathie inflammatoire démyélinisante chronique (PIDC) est une maladie rare, mais la plus fréquente des polyneuropathies dysimmunitaires chroniques. Les enjeux thérapeutiques exigent en premier lieu d’améliorer les critères du diagnostic, qui reste difficile, en particulier dans les formes atypiques. Le second enjeu est d’établir des recommandations pour le traitement de première intention, dans la mesure où les corticoïdes, les immunoglobulines intraveineuses à fortes doses (IgIV) et les échanges plasmatiques (EP) ont démontré leur efficacité dans des essais randomisés controlés. Des publications récentes ont rapporté des résultats originaux dans l’utlisation de différentes voies d’administration des corticoïdes, et également dans l’étude des délais de rechute après un traitement de première intention conduit soit avec les corticoïdes, soit avec les IgIV. Ces résultats pourraient modifier la décision thérapeutique en première intention dans les PIDC en pratique quotidienne. Le troisième enjeu, aujourd’hui le plus complexe, concerne le traitement à long-terme des PIDC, dans la mesure où aucun traitement immunomodulateur n’a démontré son efficacité. Enfin, le dernier enjeu est celui des outils d’évaluation dans les essais randomisés controlés, mais aussi en pratique clinique. L’objectif de cette revue est de faire le point sur les derniers résultats publiés dans le diagnostic, le traitement et l’évaluation des PIDC, et de donner un aperçu de la prise en charge actuelle et future des PIDC.Revue Neurologique 10/2014; · 0.60 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: Autoimmune neuropathies occur when immunologic tolerance to myelin or axonal antigens is lost. Even though the triggering factors and the underling immunopathology have not been fully elucidated in all neuropathy subsets, immunological studies on the patients' nerves, transfer experiments with the patients' serum or intraneural injections, and molecular fingerprinting on circulating autoantibodies or autoreactive T cells, indicate that cellular and humoral factors, either independently or in concert with each other, play a fundamental role in their cause. The review is focused on the main subtypes of autoimmune neuropathies, mainly the Guillain-Barré syndrome(s), the Chronic Inflammatory Demyelinating Polyneuropathy (CIDP), the Multifocal Motor Neuropathy (MMN), and the IgM anti-MAG-antibody mediated neuropathy. It addresses the factors associated with breaking tolerance, examines the T cell activation process including co-stimulatory molecules and key cytokines, and discusses the role of antibodies against peripheral nerve glycolipids or glycoproteins. Special attention is given to the newly identified proteins in the nodal, paranodal and juxtaparanodal regions as potential antigenic targets that could best explain conduction failure and rapid recovery. New biological agents against T cells, cytokines, B cells, transmigration and transduction molecules involved in their immunopathologic network, are discussed as future therapeutic options in difficult cases. This article is part of a Special Issue entitled: Neuromuscular Diseases: Pathology and Molecular Pathogenesis.Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease 06/2014; · 5.09 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: Chronic inflammatory demyelinating polyneuropathy (CIDP) is an autoimmune disease of the peripheral nervous system, in which both cellular and humoral immune responses are involved. The disease is clinically heterogeneous with some patients displaying pure motor form and others also showing a variable degree of sensory dysfunction; disease evolution may also differ from patient to patient, since monophasic, progressive, and relapsing forms are reported. Underlying such clinical variability there is probably a broad spectrum of molecular dysfunctions that are and will be the target of therapeutic strategies. In this review we first explore the biological bases of current treatments and subsequently we focus on the practical management that must also take into account pharmacoeconomic issues.Autoimmune diseases. 01/2014; 2014:201657.
Rituximab in patients with CIDP: A report of 13 cases and review of the literature
Luana Benedetti1, Chiara Briani2, Diego Franciotta3, Raffaella Fazio4, Ilaria Paolasso5,
Cristoforo Comi6, Marco Luigetti7, Mario Sabatelli7, Fabio Giannini8, Giovanni Luigi
Mancardi9, Angelo Schenone9, Eduardo Nobile-Orazio10, Dario Cocito5
1Department of Neurology, Osp. S. Andrea, La Spezia
2Department of Neurosciences, University of Padova
3 Laboratory of Neuroimmunology, IRCCS, Neurological Institute “C. Mondino”, University
of Pavia, Pavia
4Department of Neurology, IRCCS San Raffaele, Milano
5Neurologia I, Department of Neuroscience, A.S.O. San Giovanni Battista, Torino
6Interdisciplinary Research Center of Autoimmune Disease (IRCAD), A. Avogadro,
University of Eastern Piedmont, Novara
7Department of Neuroscience, Catholic University, Roma
8Department of Neuroscience, University of Siena, Siena
9Department of Neuroscience, Ophtalmology and Genetics, Genova
10Department Neurological Sciences, Milan University, IRCCS Humanitas Clinical Institute,
Key words: Rituximab, CIDP, polyradiculoneuropathy
Word Count: 1556
Luana Benedetti, M.D, PhD
Department of Neurology, Osp. S. Andrea
Via Vittorio Veneto 197, 19100 La Spezia-Italy
Tel: +39-0187-533386, Fax: +39-0187-533024. Email: email@example.com
Background: A few case reports have shown controversial results of rituximab efficacy in
patients with CIDP.
Objective: To analyze the efficacy of rituximab in a large CIDP cohort.
Methods: A retrospective, observational and multicenter study on the use of rituximab in
We treated 13 Italian CIDP patients 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 (7 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 Ig 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
Conclusions: Rituximab seems to be a promising therapeutic choice when it targets both
CIDP and co-occuring haematological diseases. Timely post-onset administration of
rituximab seems to be associated with better responses.
Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is a relapsing-
remitting, or chronic-progressive disease of the peripheral nervous system (1). The etiology
of CIDP is unknown, but immunologic mechanisms, which involve both B and T cell-
mediated responses, presumably play a central role in the pathogenesis of the damage to
peripheral myelin. Said mechanisms offer a rationale for immunoactive therapies, such as
intravenous immunoglobulins (IVIg), corticosteroids, and plasma exchange (PE), but
inadequate responses to these treatments lead to the use of immunosuppressant drugs.(2)
Rituximab, a monoclonal anti-CD20 antibody, has recently been used for the treatment of
anti-MAG antibody-associated polyneuropathy (3,4), another demyelinating neuropathy with
immune-mediated pathogenesis. In CIDP, the drug proved to be efficacious in single cases (5-
10), whereas in a prospective pilot trial (2 cases) it afforded no reduction in IVIg dosage (11).
We present 13 CIDP patients who were treated with rituximab in eight Italian centres after
unsatisfactory responses to standard therapies.
We reviewed nationally registered (12) CIDP patients diagnosed in accordance with the
EFNS/PNS criteria (13). Two of these cases had been previously reported (9,10). Table 1
summarizes the demographic and clinical characteristics of the selected 13 patients (8 men, 5
women; age range, 30-72 years, mean age, 55 years; mean neuropathy duration, 7 years).
Routine laboratory tests, including glycaemia, serum thyroid hormones, B12 vitamin, tumor
markers, and hepatitis C serology excluded other causes of neuropathy. Anti-MAG and anti-
sulfatide antibody tests were negative. Clinical impairment and disability prior to rituximab
were highly variable: mean value of 48 (range, 36-56) on the Medical Research Council
(MRC) sumscore (14), and of 5 (range, 3-8) on the Inflammatory Neuropathy Cause and
Treatment (INCAT) disability score (15). Disease course was relapsing-remitting in 9
patients, and chronic-progressive in 4. In 8 cases, CIDP co-occurred with haematological
diseases. Rituximab was proposed for the following reasons: 7 patients were refractory to
conventional immunosuppressive therapies, and quality of life was compromised to 6 patients
by frequent recourse to PE/IVIg cycles (mean between-cycle interval, 44 days; range, 14-
120); additionally, haematological diseases worsened in 4 cases. All patients gave written
informed consent to rituximab treatment.
Rituximab dosage was 375 mg/sqm IV, weekly for 4 consecutive weeks, for 12 patients;
one patient, who had severe Waldenstrom macroglobulinemia, received 1000 mg IV every six
months for 2 years (4 infusions).
Neurological assessments were performed at baseline and every month for the first 6
months, then every 3 months (MRC sumscore for muscle strength, and INCAT scales for arm
and leg disability), with ≥ 1 year follow-up. CD19+ B cells, serum immunoglobulin levels,
and platelet counts were checked regularly.
Before- and after-treatment electrophysiological data were available for 6 patients. Our
analysis was based on ulnar nerve motor conduction velocity (MCV), because peroneal nerve
MCV was not recordable in 3 patients. We considered ≥ 10% changes in MCV values as
indicators of therapeutic efficacy.
Responders were defined as those patients who improved by at least 2 points on each of
the two clinical scales, or who maintained the degrees of improvement obtained with IVIg/PE
cycles, without further cycles of IVIg/PE over the follow-up.
Our review of the literature included patients with pure CIDP, and excluded CIDP
associated with anti-MAG/-sulfatide antibodies.
Table 1 shows the clinical data. Nine out of 13 (69%) patients responded to rituximab.
Clinical improvements occurred at a median time of 2.0 months after the end of rituximab
cycles, and lasted for up to one year. Among the 7 patients who were refractory to
conventional therapies, one worsened under rituximab, whereas the other 6 improved by at
least 4 points in the MRC score, and by 2 points in the INCAT scales, with a reduction of
disability in quality-of-life-related daily activities, such as deambulation, handling knife and
fork, washing hair, and doing-undoing zips. Of the 6 patients for whom rituximab replaced
IVIg/PE cycles, 3 were responders: two patients ceased IVIg/PE and maintained the
improvement achieved with these treatments prior to rituximab (benefits started at a median
time of 2.0 months after rituximab, and lasted for ≥ 1 year); one patient stopped IVIg, and
clinically improved (10). The 3 non-responders recorded worsened clinical symptoms after a
25% reduction in IVIg dosage (Table 1). No responders required any re-treatment throughout
the follow-up period. We tried to correlate the response to rituximab with clinical variables,
namely disease duration, course of disease, and association with haematological diseases.
Mean disease durations in responders (4.3 years) were significantly shorter than in non-
responders (12.7 years; p=0.025, Mann-Whitney U test). Clinical improvement and course of
the disease did not correlate. Seven of the 9 responders, and one of the 4 non-responders had
haematological diseases, but the between-group difference was not significant (p=0.12, Fisher
Blood CD19+ B cells were undetectable in all 13 patients at month 1 post-rituximab
cycles; they reappeared at month 6, and returned to pre-treatment values at months 9-12.
Serum IgM levels were about 50% lower at 1-3 months post-treatment, and were still lower at
month 12 than at baseline in patients with IgM monoclonal gammopathy of undetermined
significance (MGUS) or with Waldenstrom macroglobulinemia. In contrast, serum IgA levels
were unchanged in the IgA MGUS patient. Platelet counts improved in the patient with
idiopathic thrombocytopenic purpura (ITP) (10). Rituximab therapy respectively
circumvented autologous peripheral blood stem cell transplantation and splenectomy in
Waldenstrom macroglobulinemia and ITP patients.
Electrophysiological data showed ≥ 10% ulnar nerve MCV improvement in 5 responders,
and worsening in one non-responder (data not shown).
No major adverse effects were recorded. During the first rituximab infusion, one patient
complained of flu-like symptoms, and another showed a mild skin allergy, which responded
B cell-depleting antibody rituximab has current FDA approval for the treatment of non-
Hodgkin lymphoma and rheumatoid arthritis, but its off-label use extends to several
autoimmune diseases. Since rituximab could target the immunological mechanisms deemed
to be involved in CIDP pathogenesis, the drug qualifies for CIDP patients who do not respond
to standard therapies. The few relevant reports show controversial results in terms of drug
efficacy. One study on 2 CIDP cases reports no benefit in the primary endpoint, namely a
25% reduction in IVIg dosage 1 year after rituximab therapy vs IVIg dosage in the year prior
to rituximab (11). In contrast, four case reports describe clinical improvement in four
rituximab-treated CIDP patients (Table 2) (5-8). Specifically, rituximab induced: the
complete disappearance of a gastric lymphoma, and long-lasting improvements in
neurological symptoms in a CIDP case (5); the remission of both neurological symptoms and
haematological abnormalities for 17 months in a patient with CIDP and Evans syndrome (6);
the stabilization of CIDP course for 11 months in a patient with diabetes mellitus (7).
Combined with chemotherapy, rituximab proved successful in a case of CIDP associated with
non-Hodgkin lymphoma (8).
To date, our cohort is the largest to be used to evaluate rituximab in CIDP. Our data show
that rituximab induced a sustained remission of neurological symptoms in about 70% of
CIDP patients. Although we do not advocate a syncretic approach, we note that this
percentage is similar to that obtainable by pooling the 6 CIDP cases previously reported in the
literature. Comparably with what was reported for anti-MAG neuropathy (16), rituximab
efficacy lasted one year, or longer, both in our series and in those previously reported in the
literature. As a result, patients either improved clinically, or were spared periodic IVIg/PE
cycles. Regarding the responders, 3 of the 6 previously reported cases, and 7 of our 13
patients, had associated haematological diseases, and rituximab was effective for both
pathologies. In all the given series, the drug was less effective for idiopathic CIDP than for
CIDP and haematological diseases. These findings suggest that, when associated with
haematological diseases, CIDP may have different pathogenic mechanisms from those
underlying isolated CIDP. Although CIDP is considered an autoimmune disease, the target
antigen and the precise roles of humoral and cell-mediated immunity remain unknown (17).
Rituximab greater efficacy in CIDP associated with haematological diseases could imply that
B cells, whether as antibody, or cytokine-producing cells, play a predominant role in the
pathogenesis of these CIDP types. Responses to rituximab in demyelinating lymphoma-
associated neuropathies (18) could support this view.
As a whole, the percentages of responders reported in the literature and in our series are
similar to those reported for anti-MAG polyneuropathy (3,4), but the intervals between
rituximab cessation and clinical improvement differed: 2-3 months in CIDP versus 6-8
months in anti-MAG polyneuropathy (3,4). It is likely that the longer intervals in anti-MAG
polyneuropathy depend on the fact that rituximab does not target plasma cells, namely the
cells directly involved in disease pathogenesis, and that benefits thus occur only after a
sustained depletion of their precursors, the CD20+ B cells.
Both for our CIDP patients and for those previously reported, mean disease duration in
responders was shorter than in non-responders. The phenomenon might derive from
cumulative axonal damage in patients with greater disease durations, and from the possible
down-regulation of CD20 molecule as a result of aggressive and prolonged pre-rituximab
immunosuppressive therapies; such down-regulation could deny targets, and hence efficacy to
In conclusion, although obtained in a relatively small number of patients, our data suggest
that rituximab therapy for refractory CIDP may be promising and free from major adverse
events, particularly if the disease has short duration, and is associated to haematological
diseases that are potentially responsive to the drug.
Competing interests: None
The Corresponding Author has the right to grant on behalf of all authors and does grant on behalf
of all authors, an exclusive licence (or non exclusive for government employees) on a worldwide
basis to the BMJ Publishing Group Ltd and its licencees, to permit this article (if accepted) to be
published in JNNP and any other BMJ Group products and to exploit all subsidiary rights, as set
out in our licence (http://jnnp.bmjjournals.com//ifora/licence.pdf)
1. Dyck PJ, Lais AC, Ohta M, et al. Chronic inflammatory polyradiculoneuropathy. Mayo
Clinic Proceedings 1975;50:621-651.
2. Brannagan TH 3rd. Current treatments of chronic immune-mediated demyelinating
polyneuropathies. Muscle Nerve 2009;39:563-78.
3. Benedetti L, Briani C, Grandis M, et al. Predictors of response to Rituximab in patients
with neuropathy and anti-MAG IgM. J Peripher Nerv Syst 2007;12:102-107.
4. Dalakas MC, Rakocevic G, Salajegheh M, et al. A placebo-controlled trial of rituximab in
IgM anti-myelin-associated glycoprotein antibody demyelinating neuropathy. Ann Neurol
5. Kilidireas C, Anagnostopoulos A, Karandreas N, et al. Rituximab therapy in monoclonal
IgM-related neuropathies. Leukemia Lymphoma 2006;47:859-864.
6. Knecht H, Baumberger M, Tobon A, et al. Sustained remission of CIDP associated with
Evans syndrome. Neurology 2004;63:730-2.
7. Műnch C, Anagnostou P, Meyer R, et al. Rituximab in chronic inflammatory
demyelinating polyneuropathy associated with diabetes mellitus. J Neurol Sci
8. Kasamon YL, Nguyen TN, Chan JA, et al. EBV-associated lymphoma and chronic
inflammatory demyelinating polyneuropathy in an adult without overt immunodeficiency.
American Journal of Hematolohy 2002;69:289-293.
9. Briani C, Zara G, Zambello R, et al. Rituximab-responsive CIDP. European Journal of
10. Benedetti L, Franciotta D, Beronio A, et al. Rituximab efficacy in CIDP associated with
idiopathic thrombocytopenic purpura. Muscle & Nerve 2008;38:1076-1077.
11. Gorson KC, Natarajan N, Ropper AH, et al. Rituximab treatment in patients with IVIg-
dependent immune polyneuropathy: a prospective pilot trial. Muscle Nerve 2007;35:66-9.
12. Cocito D, Nobile-Orazio E. Register of CIDP patient non responders to traditional therapy
(abstract). JPNS 2007;12:150-151.
13. Hughes RA, Bouche P, Cornblath DR et al. European Federation of Neurological
Societies/Peripheral Nerve Society guideline on management of chronic inflammatory
demyelinating polyradiculoneuropathy: report of a joint task force of the European
Federation of Neurological Societies and the Peripheral Nerve society. Eur J Neurol
14. Kleyweg RP, van der Mechè FGA, Schmitz PIM. Interobserver agreement in the
assessment of muscle strenght and functional abilities in Guillain-Barrè syndrome. Muscle
15. Hughes R, Bensa S, Willison H, et al, and the Inflammatory Neuropathy Cause and
Treatment (INCAT) Group. Randomized Controlled Trial of Intravenous Immunoglobulin
Versus Oral Prednilosone in Chronic Inflammatory Demyelinating
Polyradiculoneuropathy. Ann Neurol 2001;50:195-201.
16. Benedetti L, Briani C, Franciotta D, et al. Long-term effect of Rituximab in anti-MAG
polyneuropathy. Neurology 2008;71:1742-1744.
17. Hughes RA. Chronic inflammatory demyelinating polyradiculoneuropathy. Ann Neurol
18. Briani C, Zambello R, Cavallaro T, et al. Improvement of peripheral nervous system
manifestations of B-cell non-Hodgkin’s Lymphoma after Rituximab therapy. JPNS
Table 1: Demographic and clinical characteristics of the CIDP patients
To spare PE 47-53†
MRC§ INCAT§ Months
1 (M, 72)9 RR 3
B cell lymphoma
Ig M MGUS
Ster, IVIG, AZA,
Ster, IVIg, PE
Ster, PE, IVIg,
Ster, PE, IVIg,
Ster, PE, IVIg,
5-3 6 5
2 (F, 56) RR 2 6-3 6 4
3 (M, 35) RR 10 -
55-55 5-5 - 1
4 (M, 63) RR 0 -
5-2 2 4
5 (F, 65) CP 4 Ig A MGUS
56-47 3-4 - 1
6 (F, 67) CP 1
Ster, PE, IVIg
5-3 1 2
7 (M, 59)10 RR 1 ITP Ster, IVIg
5-0 1 2
8 (M, 50) RR 7
47-51† 5-3 1 2
9 (F, 30) RR 5 -
Ster, IVIg, AZA
3-1 1 1
10 (M, 65) RR 4 Ig M MGUS
Ster, IVIg, PE
6-4 2 1
11 (F, 59) CP 6 Ig M MGUS
Ster, IVIg, AZA
8-4 4 1
12 (M, 53) RR 18 -
Ster, IVIg, AZA,
Ster, IVIg, AZA,
50-50 5-5 - 1
13 (M, 45) CP 19 -
51-51 4-4 - 1
Superscript numbers in Patient column: references; RR: relapsing-remitting; CP: chronic-progressive; MGUS: monoclonal gammopathy of undetermined
significance; ITP: idiopathic thrombocytopenic purpura; IVIg: intravenous immunoglobulin; AZA: azathioprine; Cyclopho: cyclophosphamide; Ster: steroids; PE
plasma exchange; MM: mycophenolate mofetil; Cyclosp: cyclosporin; MRC: Medical Research Council sumscore; INCAT: Immune Neuropathy Cause and
Treatment arm and leg disability scores; * from the onset of neurological symptoms; §the first number refers to values at baseline, and the second number to value
at improvement; †the degree of improvement obtained after PE and IVIg cycles and maintained after rituximab; ^ which corresponded to duration of improvemen
in the responders
Table 2: Results of published studies on rituximab therapy in patients with CIDP
Author N° of
Gorson et al.
IVIg, AZA, MM,
Ster, PE, Cyclopho
No No - -
Kilidireas et al.
1 10 No
Yes 2 > 5
Knecht et al.
Ster, PE, AZA,
Yes 6 1.5
Kasamon et al.
1 < 12 Ster
Yes 2 n.a.
Műnch et al.
1 20 IVIg DM Yes 1 1
IVIg: intravenous immunoglobulin; AZA: azathioprine; Cyclopho: Cyclophosphamide; Ster: steroids; PE: plasma exchange; MM: Mycophenolate
mofetil; DM diabetes mellitus; n.a.: not available; ^ which corresponded to duration of follow-up