mycophenolic-acid and Autoimmune-Diseases-of-the-Nervous-System

Mycophenolate mofetil (MMF) and tacrolimus are novel immunosuppressive drugs, both first established in transplantation medicine and now used increasingly in neuroimmunological diseases including myasthenia gravis, dysimmune polyneuropathies, and myositis. In myasthenia gravis, the efficacy and safety of MMF has been shown by one open-label trial; one small, double-blind, placebo-controlled trial; and a few retrospective analyses. Similarly, for tacrolimus the greatest experience and evidence for efficacy and safety have been gathered in myasthenia gravis. MMF and tacrolimus have both been used as an alternative treatment for various other autoimmune diseases in which azathioprine or cyclosporine were not sufficiently effective. However, experience with tacrolimus in dysimmune polyneuropathies and myositis is limited. At this time, the available data suggest that MMF and tacrolimus are well suited for long-term immunosuppression in patients with myasthenia gravis. The spectrum of neuroimmunological diseases in which these drugs may be used has not been finally delineated and will require further controlled studies.

Topics: Autoimmune Diseases of the Nervous System; Humans; Immunosuppressive Agents; Mycophenolic Acid; Neuroimmunomodulation; Tacrolimus

To compare the efficacy and safety of different-course corticosteroids plus mycophenolate mofetil (MMF) as maintenance therapy in autoimmune encephalitis (AE) with neuronal surface antibodies (NSAbs) without tumor and explore the optimal course of corticosteroids.. Fifty-five patients with definite AE without tumor were enrolled consecutively between June 2015 and November 2020 and retrospectively divided three groups according to the course of treatment with corticosteroid, i.e., a group of patients with a course of 3-6 months (Group 3-6mo), 6-12 months (Group 6-12mo), and >12 months (Group >12mo). Demographic data, clinical manifestation and ancillary tests results were recorded. The dosage and courses of corticosteroid treatment, the recovery of neurological function, the occurrence of adverse effects, and relapses were followed up.. A total of 55 patients were included in the final analysis. The numbers of patients in Group 3-6 mo, Group 6-12 mo, and Group >12 mo was 14, 17, and 24, respectively. A significantly higher proportion of patients in Group >12 mo showed a decreased level of consciousness at the onset (12, 50%) than in Group 3-6 mo and Group 6-12 mo (2,14.3%; 3, 17.6%) (p = 0.033). The incidence of MRI abnormalities was significantly higher in Group 6-12 mo and Group >12 mo (10, 58.8%; 16, 66.7%) than in Group 3-6 mo (3, 21.4%) (P=0.023). Ordinal regression analysis indicated that decreased level of consciousness was associated with the course of corticosteroid (OR=3.838, 95% CI: 1.103-13.323, P=0.035). No significant difference was observed between the three groups regarding the cumulative dose of corticosteroids administered during the first three months of long-term treatment (P>0.05). Additionally, no significant difference in the cumulative dosage of corticosteroids was found between patients in Group 6-12 months and Group >12 months during the first 6 months after beginning long-term treatment. The mRS scores of the three groups were not statistically significant before and after first-line treatment or at the last follow-up. Bonferroni multiple comparison test indicated that the mRS scores of patients in Group 6-12 months and Group >12 months were not statistically significant at 3 months and 12 months after the start of long-term treatment. During the follow-up, 50 (90.9%) patients achieved satisfactory neurological function (mRS score ≤2). Five patients (9.1%) experienced a first relapse and 2 of them were overlapped with both anti-NMDA receptor and glial antibodies. The incidence of adverse effects was significantly higher in Group >12 mo (17, 70.8%) than in Group 3-6 mo (3, 21.4%) and Group 6-12 mo (5, 29.4%) (P=0.003).. The beneficial effects of oral corticosteroid treatment may do not persist beyond 12 months and may even contribute to an increased incidence of adverse effects. In order to optimize the effectiveness and safety of treatment, we recommend a corticosteroid course of 3-12 months. Patients with reduced levels of consciousness may be more inclined to choose longer courses of corticosteroids for long-term treatment. Patients with an "overlapping syndrome" may require more intense immunotherapy to prevent relapse.

Topics: Adrenal Cortex Hormones; Autoimmune Diseases of the Nervous System; Humans; Mycophenolic Acid; Neoplasms; Recurrence; Retrospective Studies

Topics: Adrenal Cortex Hormones; Adult; Atrophy; Autoantibodies; Autoimmune Diseases of the Nervous System; Brain; Disease Progression; Encephalomyelitis; Humans; Immunoglobulins, Intravenous; Immunologic Factors; Magnetic Resonance Imaging; Male; Mycophenolic Acid; Myelin-Oligodendrocyte Glycoprotein

Chronic inflammatory axonal polyneuropathy (CIAP) is defined on the basis of the clinical, electrophysiological and nerve biopsy findings and therapeutic responses of 'immunotherapy responding chronic axonal polyneuropathy (IR-CAP)'.. The diagnosis of IR-CAP was made when all of three of the following mandatory criterion were met: (1) acquired, chronic progressive or relapsing symmetrical or asymmetrical polyneuropathy with duration of progression >2 months; (2) electrophysiological evidence of axonal neuropathy in at least two nerves without any evidence of 'strict criteria of demyelination'; and (3) definite responsiveness to immunotherapy.. Thirty-three patients with IR-CAP showed similar clinical features of chronic inflammatory demyelinating polyneuropathy (CIDP) except 'motor neuropathy subtype'. High spinal fluid protein was found in 27/32 (78%) cases. 'Inflammatory axonal neuropathy' was proven in 14 (45%) of 31 sural nerve biopsies.. IR-CAP could well be 'axonal CIDP' in view of clinical similarity, but not proven as yet. Thus, IR-CAP is best described as CIAP, a distinct entity that deserves its recognition in view of responsiveness to immunotherapy.. Diagnosis of CIAP can be made by additional documentation of 'inflammation' by high spinal fluid protein or nerve biopsy in addition to the first two diagnostic criteria of IR-CAP.

Topics: Adolescent; Adult; Aged; Autoimmune Diseases of the Nervous System; Axons; Azathioprine; Biopsy; Child; Child, Preschool; Chronic Disease; Cyclophosphamide; Cyclosporine; Electromyography; Female; Humans; Immunoglobulins, Intravenous; Immunologic Factors; Inflammation; Male; Middle Aged; Mycophenolic Acid; Neural Conduction; Polyneuropathies; Polyradiculoneuropathy, Chronic Inflammatory Demyelinating; Sural Nerve; Young Adult

To gather data on mycophenolate mofetil (MMF) in paediatric autoimmune/immune-mediated central nervous system (CNS) conditions, focusing on safety and factors that may affect MMF efficacy.. Retrospective, multicentre study based on four paediatric neurology centres.. Forty-four children were included (30 females, 14 males): 19 had proven/suspected autoimmune encephalitis, 14 had inflammatory demyelinating CNS diseases, and 11 had other autoimmune/immune-mediated CNS conditions. Before MMF, all received first-line immune therapies, and 17 had second-line rituximab and/or cyclophosphamide. MMF was started at a median of 9.5 months from disease onset (range 1-127mo) (median age 9y 4mo, range 1y 5mo-16y 5mo), and was used for median 18 months (range 0.3-73mo). On MMF, 31 patients were relapse-free, whereas eight relapsed (excluding patients with chronic-progressive course). Relapses on MMF were associated with medication weaning/cessation, or with suboptimal MMF dosage/duration. Adverse events of MMF occurred in eight patients: six moderate (gastrointestinal, movement disorder, dermatological) and two severe (infectious).. MMF use in paediatric neuroimmunology is heterogeneous, although relatively safe. We have identified factors that may affect MMF efficacy and provide recommendations on MMF usage.. Mycophenolate mofetil (MMF) use was heterogeneous with relatively common adverse events, although mostly not severe. MMF treatment reduced median annualized relapse rate, although 20% of patients relapsed on MMF. A high relapse rate pre-MMF and late MMF start were associated with higher probability of relapsing on MMF. Most relapses were associated with suboptimal MMF dosage, short MMF duration, or concurrent medication weaning/discontinuation.. MICOFENOLATO DE MOFETILO EN ENFERMEDADES PEDIÁTRICAS AUTOINMUNES O INMUNO-MEDIADAS DEL SISTEMA NERVIOSO CENTRAL: EXPERIENCIA CLÍNICA Y RECOMENDACIONES: OBJETIVO: Recolectar información sobre el uso de Micofenolato de mofetilo (MMF) en enfermedades pediátricas del sistema nervioso central (SNC) autoinmunes o inmuno-mediadas, focalizando en la seguridad y otros factores que pudieran afectar la eficacia del MMF. MÈTODO: Estudio retrospectivo, multicéntrico, con base en cuatro centros de neurología infantil. RESULTADOS: Se incluyeron 44 niños (30 sexo femenino, 14 masculino): 19 de ellos tuvieron encefalitis autoimmune confirmada / sospechada, 14 tuvieron enfermedades inflamatorias desmielinizantes del SNC y 11 tuvieron otras condiciones autoinmunes o inmuno-mediadas del SNC. Previo al MMF todos recibieron terapias inmunológicas de primera línea, y 17 recibieron como segunda línea rituximab y / o ciclofosfamida. MMF fue iniciada a una mediana de 9.5 meses desde el comienzo de la enfermedad (rango 1-127 meses) (edad mediana 9 años y 4 meses, rango 1 año y 5 meses a 16 años y 5 meses), y fue utilizada por un tiempo mediana de 18 meses (rango 0.3 a 73 meses). Bajo MMF, 31 pacientes estuvieron libres de recidivas, mientras que 8 recidivaron (excluyendo aquellos con un curso crónico-progresivo). Las recaídas bajo el MMF estuvieron asociadas a suspensión/cese, o dosis de MMF o duración de tratamiento subóptimos. En ocho pacientes se observaron reacciones adversas al MMF: seis moderados (gastrointestinales, trastornos de movimiento o dermatológicos) y dos severos (infecciones). INTERPRETACIÓN: El uso de MMF en neuroinmunología pediátrica es heterogéneo, aunque relativamente seguro. Identificamos factores que pueden afectar la eficacia del MMF y proponemos recomendaciones sobre su uso.. MICOFENOLATO MOFETIL EM DOENÇAS PEDIÁTRICAS AUTO-IMUNES OU IMUNO-MEDIADAS DO SISTEMA NERVOSO CENTRAL: EXPERIÊNCIA CLÍNICA E RECOMENDAÇÕES: OBJETIVO: Reunir dados do micofenolato mofetil (MMF) em condições pediátricas auto-imunes ou imuno-mediadas do sistema nervoso central (SNC), com foco na segurança e nos fatores que podem afetar a eficácia do MMF. MÉTODO: Estudo restrospectivo multicêntrico baseado em quatro centros de neurologia pediátrica. RESULTADOS: Quarenta e quatro crianças foram incluídas (30 do sexo feminino, 14 do sexo masculino): 19 tiveram encefalite auto-imune comprovada/suspeita, 14 tiveram doenças inflamatórias desmielinizantes do SNC, e 11 tiveram outras condições auto-imunes ou imuno-mediadas do SNC. Antes do MMF, todas receberam imuno-terapias de primeira linha, e 17 tiveram rituximab e/ou ciclofosfamida de segunda linha. O MMF foi iniciado em uma mediana de 9.5 meses após o início da doença (variação de 1-127 meses) (idade mediana 9a 4m, variação 1a 5m a 16a 5m), e foi utilizado por uma mediana de 18 meses (variação 0.3-73m). Com MMF, 31 pacientes ficaram livres de recidivas, enquanto oito tiveram recidivas (excluídos os pacientes com curso crônico-progressivo). As recidivas com MMF forma associadas com desmame/descontinuidade da medicação, ou com dosagem/duração do MMF sub-ótimas. Efeitos adversos do MMF ocorreram em oito pacientes: seis moderados (gastrointestinal, desordem motora, dermatológico) e dois severos (infeccioso). INTERPRETAÇÃO: O uso de MMF em neuroimunologia pediátrica é heterogêneo, embora relativamente seguro. Identificamos fatores que podem afetar a eficácia do MMF e fornecemos recomendações sobre o uso de MMF.

Topics: Autoimmune Diseases of the Nervous System; Central Nervous System Diseases; Child; Female; Humans; Immunosuppressive Agents; Male; Mycophenolic Acid; Recurrence; Retrospective Studies; Treatment Outcome

Topics: Adrenal Cortex Hormones; Anti-Inflammatory Agents, Non-Steroidal; Autoantibodies; Autoimmune Diseases of the Nervous System; Brain; Disease Progression; Drug Therapy, Combination; Female; Glutamate Decarboxylase; Humans; Immunoglobulins, Intravenous; Immunologic Factors; Limbic Encephalitis; Magnetic Resonance Imaging; Male; Middle Aged; Mycophenolic Acid; Treatment Outcome; Young Adult

Autoimmune autonomic ganglionopathy is a disorder of isolated autonomic failure associated with antibodies to the nicotinic acetylcholine receptor of the autonomic ganglia resulting in severe orthostatic intolerance, syncope, constipation, gastroparesis, urinary retention, dry mouth, dry eyes, blurred vision and anhidrosis. We report the autonomic test results, antibody titers and clinical findings in 8 patients with antibodies to the nicotinic acetylcholine receptor of the autonomic ganglia. There was a sigmoidal relation between the antibody titers and the fall in systolic blood pressure (r(2)=0.84). The threshold occurred with antibody titers of approximately 1 nmol/l. Over the linear portion of the sigmoid curve, with antibody titers in the 1-3 nmol/l range, increasing antibody titers resulted in more severe orthostatic hypotension (r=0.94, P<0.001). The saturation point of the sigmoidal relation occurred at approximately 3 nmol/l with drops in systolic blood pressure of approximately 100 mmHg during upright tilt. The antibody titers correlated inversely with the Valsalva ratio (r=-0.87, P<0.001), the 30:15 ratio (r=-0.84, P<0.001) and the expiratory to inspiratory ratio (r=-0.67, P<0.01). Patients with orthostatic intolerance, anhidrosis, constipation, urinary dysfunction, sicca syndrome and pupillary dysfunction had higher antibody titers than subjects that did not (P<0.01 in all cases). Autoimmune autonomic ganglionopathy is a clinically heterogeneous disease with variable presentation, particularly in subjects with lower antibody titers. Our data suggest that patients with higher antibody titers have wide spread dysautonomia while those with lower antibody levels may present with, or evolve into, more focal or restricted presentations.

Topics: Adult; Autoantibodies; Autoantigens; Autoimmune Diseases of the Nervous System; Constipation; Disease Progression; Female; Ganglia, Autonomic; Humans; Hypohidrosis; Immunosuppressive Agents; Male; Middle Aged; Mycophenolic Acid; Phenotype; Postural Orthostatic Tachycardia Syndrome; Prednisone; Primary Dysautonomias; Pupil Disorders; Receptors, Nicotinic; Shy-Drager Syndrome; Sjogren's Syndrome; Urination Disorders

Autoimmune autonomic ganglionopathy is a disorder defined by antibodies to the nicotinic acetylcholine receptor of the autonomic ganglia. Patients present with symptoms of autonomic failure, including syncope, orthostatic hypotension, bowel and bladder hypomotility, pupillary dysfunction, and dry mouth and eyes. Symptomatic and immunomodulatory therapy has provided limited clinical benefit in small uncontrolled studies.. To investigate the effects of combined immunosuppressive therapy and plasmapheresis in autoimmune autonomic ganglionopathy.. Prospective case series.. Academic medical center.. Three patients with autoimmune autonomic ganglionopathy who had a limited response to symptomatic therapy, such as midodrine, fludrocortisone, vasopressin, and erythropoietin. Additional treatment with plasmapheresis alone and intravenous immunoglobulin alone provided no additional clinical benefit. Patients underwent 6 months of treatment with prednisone and mycophenolate mofetil followed by 5 cycles of plasma exchange.. Immunosuppressive therapy (prednisone and mycophenolate mofetil) combined with plasmapheresis resulted in substantial improvements in bowel control, pupillary function, dry mouth, and dry eyes. Mean (SD) blood pressure during immunosuppressive therapy was 162/83 (16/12) mm Hg supine and 76/45 (22/11) mm Hg standing (3 minutes). After 5 cycles of plasmapheresis, mean blood pressure was 132/82 (7/4) mm Hg supine and 127/81 (5/1) mm Hg standing (3 minutes; P < .01). Mean antibody level was 7.92 nmol/L on combined immunosuppressive therapy alone and dropped to 0.5 nmol/L after plasmapheresis.. In patients with autoimmune autonomic ganglionopathy, combining immunosuppressive medications prednisone and mycophenolate mofetil with plasmapheresis provides substantial and sustained clinical improvement that was not seen using either treatment alone. Multi-agent immunomodulatory therapies may be necessary to satisfactorily treat this immune-mediated disorder.

Topics: Adult; Autoantibodies; Autoimmune Diseases of the Nervous System; Autonomic Nervous System Diseases; Blood Pressure; Female; Ganglia, Autonomic; Heart Rate; Humans; Immunosuppressive Agents; Middle Aged; Mycophenolic Acid; Plasmapheresis; Prednisone; Prospective Studies; Tilt-Table Test; Time Factors; Treatment Outcome

Important progress has been made in our understanding of the cellular and molecular processes underlying the autoimmune neuromuscular transmission (NMT) disorders; myasthenia gravis (MG), Lambert-Eaton myasthenic syndrome (LEMS) and neuromyotonia (peripheral nerve hyperexcitability; Isaacs syndrome). To prepare consensus guidelines for the treatment of the autoimmune NMT disorders. References retrieved from MEDLINE, EMBASE and the Cochrane Library were considered and statements prepared and agreed on by disease experts and a patient representative. The proposed practical treatment guidelines are agreed upon by the Task Force: (i) Anticholinesterase drugs should be the first drug to be given in the management of MG (good practice point). (ii) Plasma exchange is recommended as a short-term treatment in MG, especially in severe cases to induce remission and in preparation for surgery (level B recommendation). (iii) Intravenous immunoglobulin (IvIg) and plasma exchange are equally effective for the treatment of MG exacerbations (level A Recommendation). (iv) For patients with non-thymomatous autoimmune MG, thymectomy (TE) is recommended as an option to increase the probability of remission or improvement (level B recommendation). (v) Once thymoma is diagnosed TE is indicated irrespective of the severity of MG (level A recommendation). (vi) Oral corticosteroids is a first choice drug when immunosuppressive drugs are necessary in MG (good practice point). (vii) In patients where long-term immunosuppression is necessary, azathioprine is recommended together with steroids to allow tapering the steroids to the lowest possible dose whilst maintaining azathioprine (level A recommendation). (viii) 3,4-diaminopyridine is recommended as symptomatic treatment and IvIg has a positive short-term effect in LEMS (good practice point). (ix) All neuromyotonia patients should be treated symptomatically with an anti-epileptic drug that reduces peripheral nerve hyperexcitability (good practice point). (x) Definitive management of paraneoplastic neuromyotonia and LEMS is treatment of the underlying tumour (good practice point). (xi) For immunosuppressive treatment of LEMS and NMT it is reasonable to adopt treatment procedures by analogy with MG (good practice point).

Topics: Adrenal Cortex Hormones; Autoimmune Diseases of the Nervous System; Azathioprine; Humans; Immunosuppressive Agents; Lambert-Eaton Myasthenic Syndrome; MEDLINE; Myasthenia Gravis; Mycophenolic Acid; Neuromuscular Junction Diseases; Plasma Exchange; Thymectomy