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Rituximab in a childhood-onset idiopathic refractory chronic inflammatory demyelinating polyneuropathy
e u r o p e a n j o u r n a l o f p a e d i a t r i c n e u r o l o g y 1 6 ( 2 0 1 2 ) 3 0 1 e3 0 3
Official Journal of the European Paediatric Neurology Society
Case study
Rituximab in a childhood-onset idiopathic refractory chronic inflammatory demyelinating polyneuropathy Adele D’Amico a,*, Michela Catteruccia a, Fabrizio De Benedetti b, Marina Vivarelli c, Manuela Colucci c, Simona Cascioli d, Enrico Bertini a a
Unit of Neuromuscular and Neurodegenerative Diseases, Department of Neurosciences, IRCCS Bambino Gesu` Pediatric Children’s Hospital, P.zza S. Onofrio 4, 00165 Rome, Italy b Laboratory of Rheumatology, IRCCS Bambino Gesu` Pediatric Children’s Hospital, P.zza S. Onofrio 4, 00165 Rome, Italy c Department of Nephrology and Urology, IRCCS Bambino Gesu` Pediatric Children’s Hospital, P.zza S. Onofrio 4, 00165 Rome, Italy d Cytometry and B-cell Development Unit, IRCCS Bambino Gesu` Pediatric Children’s Hospital, P.zza S. Onofrio 4, 00165 Rome, Italy
article info
abstract
Article history:
Childhood-onset chronic inflammatory demyelinating polyneuropathy (CIDP) are generally
Received 5 April 2011
responsive to conventional immunosuppressant treatments. However about 20% of
Received in revised form
patients may be refractory to several treatments and the disease has poor outcome. Rit-
25 July 2011
uximab is becoming a promising treatment in selected adult cases of severe CIDPs. We
Accepted 11 August 2011
report the effectiveness of Rituximab in a refractory childhood-onset CIDP and we suggest this treatment as an effective choice in unresponsive childhood CIDP.
Keywords:
ª 2011 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.
CIPD Rituximab Polineuropathy
1.
Introduction
Childhood-onset chronic inflammatory demyelinating polyneuropathy (CIDP) is an idiopathic immune-mediated neuropathy characterized by demyelination and conduction blocks as the result of peripheral nerve inflammation mediated by T cells and humoural factors. Diagnosis commonly prompts initial treatment with high dose of steroids or intravenous immunoglobulin that induce remission within 3e4 weeks in most patients.1 However, systemic side effects occur in some patients requiring long-term treatment with steroids to maintain remission. Rituximab is a humanized monoclonal antibody targeting the CD20 antigen of B cells, that has been
initially reported to be effective in the treatment of demyelinating polyneuropathy associated to IgM gammopathy.2 In the last few years increasing number of reports describe the efficacy of Rituximab in CIDPs with different immuno-mediated pathogenesis associated to haematological diseases.3
2.
Case report and results
We report on a 20 years-old girl affected by CIDP by the age of 9 years who was refractory to several immunosuppressant therapies. The first episode was characterized by acute motor ascending paralysis and sensory defect involving upper and
* Corresponding author. Tel.: þ390668592105; fax: þ390668592024. E-mail address: [email protected] (A. D’Amico). 1090-3798/$ e see front matter ª 2011 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.ejpn.2011.08.002
302
e u r o p e a n j o u r n a l o f p a e d i a t r i c n e u r o l o g y 1 6 ( 2 0 1 2 ) 3 0 1 e3 0 3
lower limbs followed by spontaneous remission within 20 days. Electrophysiological tests showed slowing of motor nerve conduction velocities and prolonged distal latencies of the median, ulnar and common peroneal nerves. Sensory nerve conduction velocities of sural and median nerves were also decreased. No F waves were evoked stimulating tibial and ulnar nerves. Cerebrospinal fluid showed elevated protein with normal count cells. A diagnosis of demyelinating polyradicolonevritis was formulated. After 1 year she sub-acutely developed paraesthesia and weakness in her left hand followed by lower limbs paralysis. Nerve conduction velocity revealed multiple conduction blocks with slowing of motor nerve conduction velocities and prolonged distal latencies in several nerves. Sensory action potentials and F waves were not evoked as well. Anti-myelin associated glycoprotein and antisulfatide antibodies were negative. Based on electrophysiological and laboratory criteria1 we formulated the diagnosis of idiopathic CIDP and 45 mg/die of oral prednisone (1.5 mg/kg/ die) was started. She presented complete remission within 1 month. After clinical remission, prednisone was progressively reduced, however when it dropped to 30 mg every other day she presented a new relapse. We decided to start intravenous immunoglobulin (0.4 g/kg/day for 5 days) but muscle weakness worsened leading to respiratory failure. Thus we decided to increase again prednisone (1.5 mg/kg/die) associating Azathioprine (2 mg/kg/die). Throughout the course of the disease she always had good response to high dose of steroids but none of the immunomodulatory and cytotoxic treatments that we tried in association, including interferon-alpha, metotrexate, and mycophenolate were helpful. The timing of treatments and the relapses have been summarized in Fig. 1. To reduce the systemic side effects of steroids we decided to treat relapses with e.v. methylprednisolone infusions (500e1000 mg/die 3day) plus mycophenolate but again she presented relapses every 2 months. Each relapse was recognized by clinical examination and confirmed by
electrophysiological tests. Most relapses were characterized by proximal weakness of lower limbs and sensory deficit of upper limbs mainly involving the median and ulnar distribution. In two occasions the patient had hypoesthesia in the facial district of trigeminal nerve. The last relapse occurred when she was treated with prednisone 30 mg every other day and mycophenolate 500 mg twice a day. Therefore, considering the poor response to conventional treatments, at the age of 19 years, we decided to treat the patient associating Rituximab (375 mg/m2/ week), despite the exclusion of a IgM monoclonal gammopathy. This treatment was approved by ethical committee of our Hospital and patient signed informed consent to receive the offlabel treatment. The patient well tolerated infusions, and no major adverse events were recorded. Peripheral CD 20þ B cells, measured by fluorescence-activated cell sorting analysis, became undetectable by the second week. Our patient, in the absence of any pharmacological treatment including steriods, continued to be relapse-free for about 1 year and the monthly count of CD20þ B cells confirmed that these were under 1%. After 1 year we observed a re-constitution of CD20þ B cells (8%) and this was followed 15 days later by a new clinical relapse. We repeated a single infusion of Rituximab that was enough to suppress most of the B cells. Patient presented clinical remission in about 1 month and she is still doing well after 6 months. In Fig. 1 we summarize relapses and therapeutic changes. The severity of relapses has been calculated using the INCAT Overall Disability Sum Score (ODSS) and reported in Fig. 1.
3.
Discussion
After the first description of a patient affected by a small lymphocytic B-cell lymphoma (CD20þ) associated to polineuropathy who presented neurological improvement following Rituximab infusion,4 this treatment has been proposed as a potential drug for refractory immune-mediated
Fig. 1 e In graphic are schematically reported the main relapses and the therapeutic changes. In ordinate are reported the INCAT disability scores. The INCAT ODSS combines arm and leg disability in a total score ranging from 0 (no signs of disability) to 12 (most severe disability score). [Merkies IS, Schmitz PI. Getting closer to patients: the INCAT Overall Disability Sum Score relates better to patients’ own clinical judgement in immune-mediated polyneuropathies. J Neurol Neurosurg Psychiatry. 2006 Aug; 77(8):970-2.] AZA, azathioprine; PDN, prednisone, IVIg, intravenous immunoglobulin; aIFN: alphainterferon, MTX, metotrexate, MM, mycophenolate mofetil; MPDS, methylprednisolone.
e u r o p e a n j o u r n a l o f p a e d i a t r i c n e u r o l o g y 1 6 ( 2 0 1 2 ) 3 0 1 e3 0 3
CIDPs associated to monoclonal gammopathy.2 In the last few years increasing number of reports describe the effectiveness of Rituximab in selected cases of CIDP and haematological disease3,4and the spectrum of potentially treatable immunemediated disorders is growing. Idiopathic childhood-onset CIDPs are clinical condition usually associated with favourable outcome, with 70e100% response to standard treatments and complete functional recovery in most patients.1 However, cases refractory to conventional therapies do exist, and additional treatments must be considered in order to improve the clinical outcome. To the best of our knowledge there is only one report of paediatric CIDP treated with Rituximab showing a partial remission.5 We describe this case to remark the importance of trying to find the best treatment in refractory CIDPs. Although no specific recommendations exist regarding this treatment, and safety and efficacy data are still insufficient, we believe that in selected patients Rituximab should be considered as a successful treatment opportunity in patients with refractory childhood CIDP.
303
references
1. Van den Bergh PY, Hadden RD, Bouche P, 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 - first revision. Eur J Neurol 2010 Mar;17(3):356e63. 2. Benedetti L, Briani C, Franciotta D, et al. Rituximab in patients with chronic inflammatory demyelinating polyradiculoneuropathy: a report of 13 cases and review of the literature. J Neurol Neurosurg Psychiatry; 2010 Jul 16. 3. Benedetti L, Franciotta D, Beronio A, et al. Rituximab efficacy in CIDP associated with idiopathic thrombocytopenic purpura. Muscle Nerve 2008;38:1076e7. 4. Briani C, Zara G, Zambello R, et al. Rituximab-responsive CIDP. Eur J Neurol 2004 Nov;11(11):788. 5. Rossignol E, D’Anjou G, Lapointe N, et al. Evolution and treatment of childhood chronic inflammatory polyneuropathy. Pediatr Neurol 2007;36:88e94.
Official Journal of the European Paediatric Neurology Society
Case study
Rituximab in a childhood-onset idiopathic refractory chronic inflammatory demyelinating polyneuropathy Adele D’Amico a,*, Michela Catteruccia a, Fabrizio De Benedetti b, Marina Vivarelli c, Manuela Colucci c, Simona Cascioli d, Enrico Bertini a a
Unit of Neuromuscular and Neurodegenerative Diseases, Department of Neurosciences, IRCCS Bambino Gesu` Pediatric Children’s Hospital, P.zza S. Onofrio 4, 00165 Rome, Italy b Laboratory of Rheumatology, IRCCS Bambino Gesu` Pediatric Children’s Hospital, P.zza S. Onofrio 4, 00165 Rome, Italy c Department of Nephrology and Urology, IRCCS Bambino Gesu` Pediatric Children’s Hospital, P.zza S. Onofrio 4, 00165 Rome, Italy d Cytometry and B-cell Development Unit, IRCCS Bambino Gesu` Pediatric Children’s Hospital, P.zza S. Onofrio 4, 00165 Rome, Italy
article info
abstract
Article history:
Childhood-onset chronic inflammatory demyelinating polyneuropathy (CIDP) are generally
Received 5 April 2011
responsive to conventional immunosuppressant treatments. However about 20% of
Received in revised form
patients may be refractory to several treatments and the disease has poor outcome. Rit-
25 July 2011
uximab is becoming a promising treatment in selected adult cases of severe CIDPs. We
Accepted 11 August 2011
report the effectiveness of Rituximab in a refractory childhood-onset CIDP and we suggest this treatment as an effective choice in unresponsive childhood CIDP.
Keywords:
ª 2011 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.
CIPD Rituximab Polineuropathy
1.
Introduction
Childhood-onset chronic inflammatory demyelinating polyneuropathy (CIDP) is an idiopathic immune-mediated neuropathy characterized by demyelination and conduction blocks as the result of peripheral nerve inflammation mediated by T cells and humoural factors. Diagnosis commonly prompts initial treatment with high dose of steroids or intravenous immunoglobulin that induce remission within 3e4 weeks in most patients.1 However, systemic side effects occur in some patients requiring long-term treatment with steroids to maintain remission. Rituximab is a humanized monoclonal antibody targeting the CD20 antigen of B cells, that has been
initially reported to be effective in the treatment of demyelinating polyneuropathy associated to IgM gammopathy.2 In the last few years increasing number of reports describe the efficacy of Rituximab in CIDPs with different immuno-mediated pathogenesis associated to haematological diseases.3
2.
Case report and results
We report on a 20 years-old girl affected by CIDP by the age of 9 years who was refractory to several immunosuppressant therapies. The first episode was characterized by acute motor ascending paralysis and sensory defect involving upper and
* Corresponding author. Tel.: þ390668592105; fax: þ390668592024. E-mail address: [email protected] (A. D’Amico). 1090-3798/$ e see front matter ª 2011 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.ejpn.2011.08.002
302
e u r o p e a n j o u r n a l o f p a e d i a t r i c n e u r o l o g y 1 6 ( 2 0 1 2 ) 3 0 1 e3 0 3
lower limbs followed by spontaneous remission within 20 days. Electrophysiological tests showed slowing of motor nerve conduction velocities and prolonged distal latencies of the median, ulnar and common peroneal nerves. Sensory nerve conduction velocities of sural and median nerves were also decreased. No F waves were evoked stimulating tibial and ulnar nerves. Cerebrospinal fluid showed elevated protein with normal count cells. A diagnosis of demyelinating polyradicolonevritis was formulated. After 1 year she sub-acutely developed paraesthesia and weakness in her left hand followed by lower limbs paralysis. Nerve conduction velocity revealed multiple conduction blocks with slowing of motor nerve conduction velocities and prolonged distal latencies in several nerves. Sensory action potentials and F waves were not evoked as well. Anti-myelin associated glycoprotein and antisulfatide antibodies were negative. Based on electrophysiological and laboratory criteria1 we formulated the diagnosis of idiopathic CIDP and 45 mg/die of oral prednisone (1.5 mg/kg/ die) was started. She presented complete remission within 1 month. After clinical remission, prednisone was progressively reduced, however when it dropped to 30 mg every other day she presented a new relapse. We decided to start intravenous immunoglobulin (0.4 g/kg/day for 5 days) but muscle weakness worsened leading to respiratory failure. Thus we decided to increase again prednisone (1.5 mg/kg/die) associating Azathioprine (2 mg/kg/die). Throughout the course of the disease she always had good response to high dose of steroids but none of the immunomodulatory and cytotoxic treatments that we tried in association, including interferon-alpha, metotrexate, and mycophenolate were helpful. The timing of treatments and the relapses have been summarized in Fig. 1. To reduce the systemic side effects of steroids we decided to treat relapses with e.v. methylprednisolone infusions (500e1000 mg/die 3day) plus mycophenolate but again she presented relapses every 2 months. Each relapse was recognized by clinical examination and confirmed by
electrophysiological tests. Most relapses were characterized by proximal weakness of lower limbs and sensory deficit of upper limbs mainly involving the median and ulnar distribution. In two occasions the patient had hypoesthesia in the facial district of trigeminal nerve. The last relapse occurred when she was treated with prednisone 30 mg every other day and mycophenolate 500 mg twice a day. Therefore, considering the poor response to conventional treatments, at the age of 19 years, we decided to treat the patient associating Rituximab (375 mg/m2/ week), despite the exclusion of a IgM monoclonal gammopathy. This treatment was approved by ethical committee of our Hospital and patient signed informed consent to receive the offlabel treatment. The patient well tolerated infusions, and no major adverse events were recorded. Peripheral CD 20þ B cells, measured by fluorescence-activated cell sorting analysis, became undetectable by the second week. Our patient, in the absence of any pharmacological treatment including steriods, continued to be relapse-free for about 1 year and the monthly count of CD20þ B cells confirmed that these were under 1%. After 1 year we observed a re-constitution of CD20þ B cells (8%) and this was followed 15 days later by a new clinical relapse. We repeated a single infusion of Rituximab that was enough to suppress most of the B cells. Patient presented clinical remission in about 1 month and she is still doing well after 6 months. In Fig. 1 we summarize relapses and therapeutic changes. The severity of relapses has been calculated using the INCAT Overall Disability Sum Score (ODSS) and reported in Fig. 1.
3.
Discussion
After the first description of a patient affected by a small lymphocytic B-cell lymphoma (CD20þ) associated to polineuropathy who presented neurological improvement following Rituximab infusion,4 this treatment has been proposed as a potential drug for refractory immune-mediated
Fig. 1 e In graphic are schematically reported the main relapses and the therapeutic changes. In ordinate are reported the INCAT disability scores. The INCAT ODSS combines arm and leg disability in a total score ranging from 0 (no signs of disability) to 12 (most severe disability score). [Merkies IS, Schmitz PI. Getting closer to patients: the INCAT Overall Disability Sum Score relates better to patients’ own clinical judgement in immune-mediated polyneuropathies. J Neurol Neurosurg Psychiatry. 2006 Aug; 77(8):970-2.] AZA, azathioprine; PDN, prednisone, IVIg, intravenous immunoglobulin; aIFN: alphainterferon, MTX, metotrexate, MM, mycophenolate mofetil; MPDS, methylprednisolone.
e u r o p e a n j o u r n a l o f p a e d i a t r i c n e u r o l o g y 1 6 ( 2 0 1 2 ) 3 0 1 e3 0 3
CIDPs associated to monoclonal gammopathy.2 In the last few years increasing number of reports describe the effectiveness of Rituximab in selected cases of CIDP and haematological disease3,4and the spectrum of potentially treatable immunemediated disorders is growing. Idiopathic childhood-onset CIDPs are clinical condition usually associated with favourable outcome, with 70e100% response to standard treatments and complete functional recovery in most patients.1 However, cases refractory to conventional therapies do exist, and additional treatments must be considered in order to improve the clinical outcome. To the best of our knowledge there is only one report of paediatric CIDP treated with Rituximab showing a partial remission.5 We describe this case to remark the importance of trying to find the best treatment in refractory CIDPs. Although no specific recommendations exist regarding this treatment, and safety and efficacy data are still insufficient, we believe that in selected patients Rituximab should be considered as a successful treatment opportunity in patients with refractory childhood CIDP.
303
references
1. Van den Bergh PY, Hadden RD, Bouche P, 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 - first revision. Eur J Neurol 2010 Mar;17(3):356e63. 2. Benedetti L, Briani C, Franciotta D, et al. Rituximab in patients with chronic inflammatory demyelinating polyradiculoneuropathy: a report of 13 cases and review of the literature. J Neurol Neurosurg Psychiatry; 2010 Jul 16. 3. Benedetti L, Franciotta D, Beronio A, et al. Rituximab efficacy in CIDP associated with idiopathic thrombocytopenic purpura. Muscle Nerve 2008;38:1076e7. 4. Briani C, Zara G, Zambello R, et al. Rituximab-responsive CIDP. Eur J Neurol 2004 Nov;11(11):788. 5. Rossignol E, D’Anjou G, Lapointe N, et al. Evolution and treatment of childhood chronic inflammatory polyneuropathy. Pediatr Neurol 2007;36:88e94.