Time course of the autoantibody response to therapy in anti-MAG neuropathy: TWO case REPORTS.

Background: Anti-MAG neuropathy is a slowly progressive demyelinating neuropathy that can lead to disability. The neuropathy is thought to be caused by monoclonal IgM antibodies that target the Myelin Associated Glycoprotein (MAG) in peripheral nerves. Therapy is directed at lowering the autoantibody concentrations with B-cells depleting agents, most often rituximab, based on case series and uncontrolled trials reporting improvement. There are no FDA approved treatments for anti-MAG neuropathy, however, and two relatively short duration randomized controlled trials with rituximab failed to achieve their pre-specified primary endpoints. There is also little information regarding the number or duration of treatments that are required to effectively reduce the antibody concentrations. Case presentations: We report the time course of the anti-MAG antibody response in two patients with anti-MAG neuropathy that were treated with rituximab for several years. A reduction of 50% in the anti-MAG IgM was seen after 19 and 58 months respectively, and of 70% after 74 or 104 months of treatment respectively. Titres remained low, without evidence of recurrence after the treatments were discontinued. Conclusion: Therapy of anti-MAG neuropathy with rituximab may require repeat treatments over more than one year to achieve a significant reduction in autoantibody concentrations. These considerations should inform treatment decisions and the design of clinical trials.

Anti-MAG neuropathy: historical aspects, clinical-pathological correlations, and considerations for future therapeutical trials.

BACKGROUND: Patients with anti-MAG neuropathy present with distal demyelinating polyneuropathy, IgM monoclonal gammopathy, and elevated titers of anti-MAG antibodies. OBJECTIVE: This paper reviews what is known about the clinical presentation, course, pathophysiology, and treatment of anti-MAG neuropathy, with considerations for the design of therapeutic trials. METHODS: A literature review of the medical and scientific literature related to anti-MAG neuropathy, and the design of therapeutic clinical trials in peripheral neuropathy. RESULTS: Anti-MAG neuropathy can remain indolent for many years but then enter a progressive phase. Highly elevated antibody titers are diagnostic, but intermediate titers can also occur in chronic inflammatory demyelinating polyneuropathy (CIDP). The peripheral nerves can become inexcitable, thereby masking the demyelinating abnormalities. There is good evidence that the anti-MAG antibodies cause neuropathy. Reduction of the autoantibody concentration by agents that target B-cells was reported to result in clinical improvement in case series and uncontrolled trials, but not in controlled clinical trials, probably due to inadequate trial design. CONCLUSION: We propose that therapeutic trials for anti-MAG neuropathy include patients with the typical presentation, some degree of weakness, highly elevated anti-MAG antibody titers, and at least one nerve exhibiting demyelinating range abnormalities. Treatment with one or a combination of anti-B-cell agents would aim at reducing the autoantibody concentration by at least 60%. A trial duration of 2 years may be required to show efficacy. The neuropathy impairment score of the lower extremities (NIS-LL) plus the Lower Limb Function (LLF) score would be a suitable primary outcome measure.

ANTECEDENTES: Pacientes com neuropatia anti-MAG apresentam polineuropatia desmielinizante distal, gamopatia monoclonal IgM e títulos elevados de anticorpos anti-MAG. OBJETIVO: Este artigo revisa o que se sabe sobre a apresentação clínica, curso, fisiopatologia e tratamento da neuropatia anti-MAG, com considerações para o desenho de ensaios terapêuticos. MéTODOS: Revisão bibliográfica da literatura médica e científica relacionada à neuropatia anti-MAG e desenho de ensaios clínicos terapêuticos em neuropatia periférica. RESULTADOS: A neuropatia anti-MAG pode permanecer indolente durante muitos anos, mas depois entra numa fase progressiva. Títulos de anticorpos altamente elevados são diagnósticos, mas títulos intermediários também podem ocorrer na polineuropatia desmielinizante inflamatória crônica (CIDP). Os nervos periféricos podem tornar-se inexcitáveis, mascarando, assim, as anomalias desmielinizantes. Há boas evidências de que os anticorpos anti-MAG causam a neuropatia. Foi relatado que a redução da concentração de autoanticorpos por agentes direcionados às células B resultou em melhora clínica em séries de casos e ensaios não controlados, mas não em ensaios clínicos controlados, provavelmente devido ao desenho inadequado dos ensaios. CONCLUSãO: Propomos que os ensaios terapêuticos para neuropatia anti-MAG incluam pacientes com apresentação típica, algum grau de fraqueza, títulos de anticorpos anti-MAG altamente elevados e pelo menos um nervo exibindo anormalidades na faixa desmielinizante. O tratamento com um ou uma combinação de agentes anticélulas B teria como objetivo reduzir a concentração de autoanticorpos em pelo menos 60%. Pode ser necessária uma duração de ensaio de 2 anos para demonstrar eficácia. A pontuação de comprometimento da neuropatia das extremidades inferiores (NIS-LL) mais a pontuação da função dos membros inferiores (LLF) seria uma medida de resultado primário adequada.

Hyaluronidase-facilitated subcutaneous immunoglobulin 10% as maintenance therapy for chronic inflammatory demyelinating polyradiculoneuropathy: The ADVANCE-CIDP 1 randomized controlled trial.

BACKGROUND AND AIMS: ADVANCE-CIDP 1 evaluated facilitated subcutaneous immunoglobulin (fSCIG; human immunoglobulin G 10% with recombinant human hyaluronidase) efficacy and safety in preventing chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) relapse. METHODS: ADVANCE-CIDP 1 was a phase 3, double-blind, placebo-controlled trial conducted at 54 sites in 21 countries. Eligible adults had definite or probable CIDP and adjusted Inflammatory Neuropathy Cause and Treatment (INCAT) disability scores of 0-7 (inclusive), and received stable intravenous immunoglobulin (IVIG) for ≥12 weeks before screening. After stopping IVIG, patients were randomized 1:1 to fSCIG 10% or placebo for 6 months or until relapse/discontinuation. fSCIG 10% was administered at the same dose (or matching placebo volume) and interval as pre-randomization IVIG. The primary outcome was patient proportion experiencing CIDP relapse (≥1-point increase in adjusted INCAT score from pre-subcutaneous treatment baseline) in the modified intention-to-treat population. Secondary outcomes included time to relapse and safety endpoints. RESULTS: Overall, 132 patients (mean age 54.4 years, 56.1% male) received fSCIG 10% (n = 62) or placebo (n = 70). CIDP relapse was reduced with fSCIG 10% versus placebo (n = 6 [9.7%; 95% confidence interval 4.5%, 19.6%] vs n = 22 [31.4%; 21.8%, 43.0%], respectively; absolute difference: -21.8% [-34.5%, -7.9%], p = .0045). Relapse probability was higher with placebo versus fSCIG 10% over time (p = .002). Adverse events (AEs) were more frequent with fSCIG 10% (79.0% of patients) than placebo (57.1%), but severe (1.6% vs 8.6%) and serious AEs (3.2% vs 7.1%) were less common. INTERPRETATION: fSCIG 10% more effectively prevented CIDP relapse than placebo, supporting its potential use as maintenance CIDP treatment.

Correction: Latov, N. Campylobacter jejuni Infection, Anti-Ganglioside Antibodies, and Neuropathy. Microorganisms 2022, 10, 2139.

The authors wish to make the following corrections to this paper [...].

Campylobacter jejuni Infection, Anti-Ganglioside Antibodies, and Neuropathy.

Preceding infection with Campylobacter jejuni (Cj) occurs in approximately 30% of patients with Guillain-Barre syndrome (GBS), and the risk of GBS following Cj infection is increased by 77 to 100-fold. GBS is most often of the axonal subtype and is thought to be mediated by IgG antibodies to peripheral nerve gangliosides that are cross reactive with oligosaccharides in the Cj lipopolysaccharides (LPS). The antibodies are thought to be induced by molecular mimicry, where immune reactivity to a cross reactive epitope in the infectious organism and normal tissue can cause autoimmune disease. Clonally restricted IgM antibodies that react with the same oligosaccharides in gangliosides and Cj-LPS are associated with chronic neuropathies of otherwise similar phenotypes. The anti-ganglioside antibodies in GBS are of the IgG1 and IgG3 subclasses, indicating T-cell reactivity to the same antigens that could help disrupt the blood-nerve barrier. Cj infection can activate multiple innate and adoptive pro-inflammatory pathways that can overcome immune tolerance and induce autoimmunity. Elucidation of the specific immune mechanisms involved in the development of the autoantibodies and neuropathy would help our understanding of the relation between infection and autoimmunity and aid in the development of more effective preventive interventions and therapies.

Intravenous immunoglobulin in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP): mechanisms of action and clinical and genetic considerations.

INTRODUCTION: Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is an autoimmune peripheral nerve disorder that is characterized by subacute onset, progressive or relapsing weakness, and sensory deficits. Proven treatments include intravenous immunoglobulin (IVIg), corticosteroids, and plasma exchange. This review focuses on the mechanisms of action, pharmacodynamics, genetic variations, and disease characteristics that can affect the efficacy of IVIg. AREAS COVERED: The proposed mechanisms of action of IVIg that can mediate its therapeutic effects are reviewed. These include anti-idiotypic interactions, inhibition of neonatal Fc receptors (FcRn), anti-complement activity, upregulation of inhibitory FcγRIIB receptors, and downregulation of macrophage activation or co-stimulatory and adhesion molecules. Clinical and genetic factors that can affect the therapeutic response include misdiagnosis, degree of axonal damage, pharmacokinetic variability, and genetic variations. EXPERT OPINION: The mechanisms of action of IVIg in CIDP and their relative contribution to its efficacy are subject of ongoing investigation. Studies in other autoimmune neurological conditions, in addition, highlight the role of key immunopathological pathways and factors that are likely to be affected. Further investigation into the pathogenesis of CIDP and the mechanisms of action of IVIg may lead to the development of improved diagnostics, better utilization of IVIg, and more targeted and effective therapies.

Immune mechanisms, the role of complement, and related therapies in autoimmune neuropathies.

INTRODUCTION: Autoimmune neuropathies have diverse presentations and underlying immune mechanisms. Demonstration of efficacy of therapeutic agents that inhibit the complement cascade would confirm the role of complement activation. AREAS COVERED: A review of the pathophysiology of the autoimmune neuropathies, to identify those that are likely to be complement mediated. EXPERT OPINION: Complement mediated mechanisms are implicated in the acute and chronic neuropathies associated with IgG or IgM antibodies that target the Myelin Associated Glycoprotein (MAG) or gangliosides in the peripheral nerves. Antibody and complement mechanisms are also suspected in the Guillain-Barré syndrome and chronic inflammatory demyelinating neuropathy, given the therapeutic response to plasmapheresis or intravenous immunoglobulins, even in the absence of an identifiable target antigen. Complement is unlikely to play a role in paraneoplastic sensory neuropathy associated with antibodies to HU/ANNA-1 given its intracellular localization. In chronic demyelinating neuropathy with anti-nodal/paranodal CNTN1, NFS-155, and CASPR1 antibodies, myotonia with anti-VGKC LGI1 or CASPR2 antibodies, or autoimmune autonomic neuropathy with anti-gAChR antibodies, the response to complement inhibitory agents would depend on the extent to which the antibodies exert their effects through complement dependent or independent mechanisms. Complement is also likely to play a role in Sjogren's, vasculitic, and cryoglobulinemic neuropathies.

Antibody testing in neuropathy associated with anti-Myelin-Associated Glycoprotein antibodies: where we are after 40 years.

PURPOSE OF REVIEW: The diagnosis of Myelin-Associated Glycoprotein (MAG) neuropathy is based on the presence of elevated titers of IgM anti-MAG antibodies, which are typically associated with IgM monoclonal gammopathy, and a slowly progressive, distal demyelinating phenotype. The condition, however, can be under or over diagnosed in patients with mildly elevated antibody titers, absent monoclonal gammopathy, or an atypical presentation. The purpose of this paper is to examine recent advances in our understanding of the currently available anti-MAG antibody assays, their reliability, and their use in deciding treatment or monitoring the response to therapy. RECENT FINDINGS: Higher titers of anti-MAG antibodies are more likely to be associated with the typical MAG phenotype or response to therapy. Mildly elevated antibody levels can occur in patients with chronic inflammatory demyelinating polyneuropathy. Testing for cross-reactivity with HNK1 can add to the specificity of the antibody assays. Patients with MAG neuropathy can present with an atypical phenotype and in the absence of a detectable monoclonal gammopathy. SUMMARY: Assays for anti-MAG antibodies by Enzyme-Linked Immunosorbent Assay can be improved by testing for antibody binding at multiple serum dilutions, the inclusion of antigen-negative microwells as internal controls for each sample, testing for cross-reactivity with HNK1, and formal validation. The diagnosis needs to be considered in patients with demyelinating neuropathy, even in the absence of a monoclonal gammopathy or typical phenotype. The change in antibody levels needs to be considered in evaluating the response to therapy with B-cell depleting agents.

Relapsing Bickerstaff Brainstem Encephalitis After Autologous Stem Cell Transplant.

Bickerstaff brainstem encephalitis, widely considered to be associated with Miller Fisher and Guillain-Barré syndromes, is a rare disease state defined by the triad of ophthalmoplegia, ataxia, and decreased consciousness. The presence of central nervous system involvement, commonly in the form of impaired arousal, solidifies it as a unique entity. We present a case of this rare syndrome after autologous stem cell transplant.

FGFR3 autoantibodies in sensory neuronopathy.

FGFR3 antibodies have been associated with sensory neuropathy, but many questions remain regarding their use in clinical practice.

Oral fingolimod for chronic inflammatory demyelinating polyradiculoneuropathy (FORCIDP Trial): a double-blind, multicentre, randomised controlled trial.

BACKGROUND: Fingolimod is approved for the treatment of relapsing-remitting multiple sclerosis and was effective in experimental autoimmune neuritis in rats, a possible model for chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). We aimed to evaluate the efficacy of fingolimod in delaying disability progression in patients with CIDP who withdrew from currently effective treatments (intravenous immunoglobulin [IVIg] or corticosteroids). METHODS: This double-blind, multicentre, randomised, placebo-controlled, parallel-group, event-driven study was done at 48 neurology centres in Australia, Canada, Israel, Japan, the USA, and nine countries in Europe. Participants with CIDP who were receiving IVIg or corticosteroids were randomly assigned (1:1) to once-daily oral fingolimod 0·5 mg or placebo. Owing to the event-driven design, treatment duration was flexible and could be up to 4·5 years. Randomisation was done with an automated interactive voice response-web response system and was stratified by Inflammatory Neuropathy Cause and Treatment (INCAT) disability scale scores. Previous IVIg treatment was discontinued after one final course ending the day before the first dose of fingolimod or placebo was given, whereas corticosteroids were tapered off over 8 weeks after randomisation. The primary endpoint was time to first confirmed worsening (≥1 point increase on the adjusted INCAT disability scale score versus baseline) and was assessed in the full analysis set, which consisted of all patients who underwent randomisation and had at least one efficacy assessment for the primary analysis. The survival distribution functions of time to first worsening were estimated within each treatment group according to the Kaplan-Meier survival distribution function and compared with a stratified log-rank test. The trial is registered with ClinicalTrials.gov, number NCT01625182. FINDINGS: Of 106 participants randomly assigned between Jan 24, 2013, and March 10, 2016, 54 received fingolimod (41 who had been receiving IVIg and 13 who had been receiving corticosteroids) and 52 received placebo (41 who had been receiving IVIg and 11 who had been receiving corticosteroids). The trial ended for futility as recommended by an independent data monitoring committee after an interim analysis when 44 confirmed worsening events had occurred. At the end of the study, the survival estimate of the proportion of participants free from confirmed worsening was not significantly different between the fingolimod group (42%, 95% CI 23-60) and the placebo group (43%, 28-59; p=0·91). Adverse events occurred in 41 (76%) participants receiving fingolimod and 44 (85%) on placebo, and serious adverse events occurred in nine (17%) and four (8%) patients, respectively. The most common adverse events with fingolimod were headache (12 [22%] patients), hypertension (ten [19%]), and extremity pain (seven [13%]). Adverse events leading to study discontinuation occurred in seven (13%) participants on fingolimod and none on placebo. INTERPRETATION: Fingolimod 0·5 mg once-daily was not better than placebo for the treatment of CIDP. Future trial designs should take account of the possibility that if IVIg is stopped abruptly, some patients might relapse soon afterwards whereas others might remain in remission. FUNDING: Novartis Pharma.

Changes in spatiotemporal gait parameters following intravenous immunoglobulin treatment for chronic inflammatory demyelinating polyneuropathy.

INTRODUCTION: Gait impairment is a common presenting symptom in patients with chronic inflammatory demyelinating polyneuropathy (CIDP). However, gait parameters have not previously been evaluated in detail as potential independent outcome measures. METHODS: We prospectively measured changes in spatiotemporal gait parameters of 20 patients with CIDP at baseline and following treatment with intravenous immunoglobulin (IVIG), using GAITRite® a computerized walkway system with embedded sensors. RESULTS: Overall, study patients showed significant improvements in gait velocity, cadence, stride length, double support time, stance phase, and swing phase following IVIG treatment. Mean changes in velocity, stance phase, and swing phase, exhibited the greatest statistical significance among the subgroup that exhibited clinically meaningful improvement in Inflammatory Neuropathy Cause and Treatment disability score, Medical Research Council sum score, and grip strength. CONCLUSIONS: Assessment of gait parameters, in particular velocity, step phase and swing phase, is a potentially sensitive outcome measure for evaluating treatment response in CIDP. Muscle Nerve 56: 732-736, 2017.

Measuring disease activity and clinical response during maintenance therapy in CIDP: from ICE trial outcome measures to future clinical biomarkers.

Some patients with chronic inflammatory demyelinating polyradiculoneuropathy who respond to initial intravenous immunoglobulin require repeated courses over prolonged periods of time; however, evidence to guide dosage and interval of intravenous immunoglobulin during maintenance therapy is limited. Optimizing treatment requires assessment of underlying disease activity and clinical outcome. Electrophysiological measures of demyelination, and clinical measures using handgrip strength and walking velocity promise to be particularly informative. Major advances in resolution and image processing have expanded clinical applications for ultrasound to include the study of peripheral nerves. Ultrasonography shows promise in diagnosing chronic inflammatory demyelinating polyradiculoneuropathy and distinguishing it from other conditions, providing first ever insight into gross pathology of peripheral nerves. Ultrasonography may also have a role in monitoring disease activity and treatment response.

Abnormal Nutritional Factors in Patients Evaluated at a Neuropathy Center.

Abnormal concentrations of nutritional factors were found in 24.1% of 187 patients with neuropathy who were newly seen at our academic neuropathy referral center over a 1-year period. All patients presented with sensory axonal or small fiber neuropathy. In 7.3%, they were present in association with at least one other identifiable cause for neuropathy. Elevated levels of pyridoxal phosphate or mercury occurred more frequently than deficiencies in vitamins B1, B12, or B6. The nutritional abnormalities are amenable to correction by dietary intervention.

Correlation of Changes in Gait Parameters, With Phenotype, Outcome Measures, and Electrodiagnostic Abnormalities in a Patient With Anti-MAG Neuropathy After Exacerbation and Improvement.

Gait impairment is a common presentation in patients with IgM anti-myelin-associated glycoprotein (anti-MAG) antibody demyelinating neuropathy. However, current methods used to assess gait are limited. We report spatiotemporal gait parameters captured by GAITRite, a computerized walkway with embedded pressure sensors. The patient worsened after treatment with rituximab and subsequently improved with intravenous immunoglobulin. Serial gait assessments were performed at baseline and after treatment. Spatiotemporal gait parameters correlated with Medical Research Council sum score, Inflammatory Neuropathy Cause and Treatment disability score, and grip strength. Quantitative gait assessment may provide a new dimension to standard clinical evaluation and may help to clarify treatment response in patients with anti-MAG neuropathy when used in combination with other validated assessment tools.

Follow-up nerve conduction studies in CIDP after treatment with IGIV-C: Comparison of patients with and without subsequent relapse.

INTRODUCTION: Electrodiagnostic studies (EDX) are not performed routinely before treatment suspension in CIDP, and no data exist regarding their value in predicting clinical relapse. METHODS: Serial EDX (baseline and after IGIV-C therapy) were analyzed from subjects in the ICE clinical trial who responded to IGIV-C treatment and were subsequently re-randomized to placebo in an extension phase. Comparisons were made between subjects who relapsed and those who did not. RESULTS: A total of 55% (6/11) of the Relapse group had an increase in total number of demyelinating findings (DF) versus 8% (1/13) in the No Relapse group (P = 0.023). In the Relapse group, 100% had ≥ 1 new DF and 73% (8/11) had ≥ 4 new DF versus 60% (8/13) and 8% (1/13), respectively, in the No Relapse group. CONCLUSIONS: An increased total number of DF or the occurrence of ≥ 4 new DF may indicate a higher risk of clinical relapse after treatment cessation in IGIV-C-responsive patients.

Comparison of 2-limb versus 3-limb electrodiagnostic studies in the evaluation of chronic inflammatory demyelinating polyneuropathy.

INTRODUCTION: European Federation of Neurological Societies/Peripheral Nerve Society electrodiagnostic (EDx) criteria for the definite diagnosis of chronic inflammatory demyelinating polyneuropathy (CIDP) require the presence of demyelinating findings (DF) in at least 2 nerves. Data are lacking, however, regarding the optimal number of nerves to test. METHODS: We retrospectively reviewed EDx data from 53 patients with CIDP and compared the number of DF found on 2- and 3-limb testing. RESULTS: A median of 3 (range 2-5) DF were found on 2-limb testing compared with 5 (range 4-7) DF when 3 limbs were evaluated. Two-limb EDx studies were sufficient to diagnose definite CIDP in 92.3% of typical, 84.2% of asymmetric, and 66.7% of distal phenotypes. Testing a third limb increased diagnostic certainty in 11 patients (20.8%) to definite CIDP. CONCLUSIONS: Three-limb testing may increase diagnostic sensitivity of definite CIDP, especially in patients with atypical phenotypes. Larger prospective studies are needed to better assess the benefit of performing 3-limb EDx studies.