Obinutuzumab, a potent anti-B-cell agent, for rituximab-unresponsive IgM anti-MAG neuropathy.

Anti-MAG demyelinating neuropathy is difficult to treat. All immunotherapies have failed except for rituximab, a chimeric B-cell–depleting monoclonal antibody against CD20, that helps up to 40% of patients based on 2 controlled and several uncontrolled series.1,–,3 Because the majority of these patients are left disabled, stronger anti–B-cell agents might be promising. We describe clinical response and autoantibody changes after treatment with obinutuzumab (Gazyva), a new generation of humanized anti-CD20 monoclonal antibodies, in 2 patients with anti-MAG neuropathy who continued to worsen despite multiple courses of rituximab. Obinutuzumab, approved for chronic lymphocytic leukemia (CLL), exerts greater peripheral and lymphoid B-cell depletion4 and might be more effective in rituximab-refractory patients. © Rakocevic et al

Inflammatory myopathies: update on diagnosis, pathogenesis and therapies, and COVID-19-related implications.

The inflammatory myopathies constitute a heterogeneous group of acquired myopathies that have in common the presence of endomysial inflammation. Based on steadily evolved clinical, histological and immunopathological features and some autoantibody associations, these disorders can now be classified in five characteristic subsets: Dermatomyositis (DM) Polymyositis (PM), Necrotizing Autoimmune Myositis (NAM), Anti-synthetase syndrome-overlap myositis (Anti-SS-OM), and Inclusion-Body-Myositis (IBM). Each inflammatory myopathy subset has distinct immunopathogenesis, prognosis and response to immunotherapies, necessitating the need to correctly identify each subtype from the outset to avoid disease mimics and proceed to early therapy initiation. The review presents the main clinicopathologic characteristics of each subset highlighting the importance of combining expertise in clinical neurological examination with muscle morphology and immunopathology to avoid erroneous diagnoses and therapeutic schemes. The main autoimmune markers related to autoreactive T cells, B cells, autoantibodies and cytokines are presented and the concomitant myodegenerative features seen in IBM muscles are pointed out. Most importantly, unsettled issues related to a role of autoantibodies and controversies with reference to possible triggering factors related to statins are clarified. The emerging effect SARS-CoV-2 as the cause of hyperCKemia and potentially NAM is addressed and practical guidelines on the best therapeutic approaches and concerns regarding immunotherapies during COVID-19 pandemic are summarized

Comment: Humoral and T-cell Immunities to SARS-CoV-2 Vaccines: Safety, Efficacy, and Challenges in Autoimmune Neurology

With the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) messenger RNA (mRNA)vaccinations, we have been witnessing a new era in vaccinology because these vaccines do not contain viral proteins but mRNA or viral vectors that instruct the cells to make viralspecific protective antibodies. To effectively fight SARS-CoV-2 infection, however, these vaccines need to induce both humoral and cell-mediated immune responses, with antibodies that block viral replication and viral-specific T cells that kill viral-infected cells and generate antibodyproducing plasma cells and long-lived memory cells

Objectivity, Practicality, and Significance of Practice Guidelines for the Practicing Neurologists: What We Learnt From Consensus Criteria in CIDP, Myasthenia Gravis and Inflammatory Myopathies

The value of practice guidelines in the three most common autoimmune neuromuscular disorders, namely Chronic Inflammatory Demyelinating Polyneuropathy (CIDP), Myasthenia Gravis (MG) and Autoimmune Inflammatory Myopathies (AIM), has been extensively debated regarding their usefulness in clinical practice, objectivity and universal value considering that guidelines are also established regionally in certain countries. This commentary highlights common concerns on how guidelines are presently generated, pointing out: (a) non-sufficient diversity among Task-Force members to identify and address not only routine clinical and electrophysiology issues but also immunology, imaging, pathology, biomarkers, epidemiology or treatment economics; (b) Task-Force being often comprised by the same or seemingly like-minded members conveying the erroneous impression that experts with opposing views might have been excluded, even if this is clearly not the case; and (c) relying on web-based registries or retrospective data collections from heterogeneous sources. As a result, the existing practice guidelines in CIDP, MG and AIM remain an unfinished business but an excellent base for further enhancement. Guidelines can be extremely helpful not only for clinical trials but also in clinical practice if viewed as a living document with continuously updated versions by experts even with opposing views with precise information on diagnostics, pathomechanisms, therapeutic schemes, evolving biomarkers and economics of new therapies with validation of the post-guidelines criteria. Geographic diversity should be taken into consideration because the availability of biomarker testing, and therapies differ among countries. Patient preferences need to be also considered in therapeutic guidelines because newly marketed drugs offer more options steadily changing the therapeutic algorithms in autoimmune neuromuscular diseases generating also questions as to whether they also influence decisions on insurance coverage. Collectively, these startup considerations are aimed to make practice guidelines more objective, widely acceptable worldwide and more practical or easier to follow in clinical practice

The importance of FcRn in neuro-immunotherapies: From IgG catabolism, FCGRT gene polymorphisms, IVIg dosing and efficiency to specific FcRn inhibitors.

The neonatal Fc receptor (FcRn) binds endogenous IgG and protects it from lysosomal degradation by transporting it back to the cell surface to re-enter the circulation, extending the serum IgG life span. FcRn plays a role in the function of IVIg because the supraphysiological IgG levels derived from IVIg administrations saturate the FcRn allowing the endogenous IgG to be degraded, instead of being recycled, resulting in high levels of infused IgG ensuring IVIg efficiency. New data in myasthenia gravis patients suggest that the that the Variable Number of Tandem 3/2 (VNTR3/2) polymorphisms in FCGRT, the gene that encodes FcRn, may affect the duration of infused IgG in the circulation and IVIg effectiveness. This review addresses these implications in the context of whether the FCGRT genotype, by affecting the half-life of IVIg, may also play a role in up to 30% of patients with autoimmune neurological diseases, such as Guillain-Barré syndrome, CIDP or Multifocal Motor Neuropathy, who did not respond to IVIg in controlled trials. The concern is of practical significance because in such patient subsets super-high IVIg doses may be needed to achieve high IgG levels and ensure efficacy. Whether FCGRT polymorphisms affect the efficacy of other therapeutic monoclonal antibodies by influencing their distribution clearance and pharmacokinetics, explaining their variable effectiveness, is also addressed. Finally, the very promising effect of monoclonal antibodies that inhibit FcRn, such as efgartigimod, rozanolixizumab and nipocalimab, in treating antibody-mediated neurological diseases is discussed along with their efficacy in the IgG4 subclass of pathogenic antibodies and their role in the blood-brain barrier endothelium, that abundantly expresses FcRn

Severe Stiff-Person Syndrome After COVID: The First Video-Documented COVID Exacerbation and Viral Implications

OBJECTIVES: To describe a patient with mild GAD-positive stiff-leg syndrome (SLS) who developed severely disabling stiff-person syndrome (SPS) 1 week after mild COVID-19 and discuss the impact of viral implications. METHODS: Video-documented serial clinical observations at baseline, after acute COVID-19, and after IVIG treatments. RESULTS: A 39-year-old man with left-SLS was stable during a 2-year follow-up with low-dose antispasmodics, working fully and functioning normally, even able to run. One week after mild COVID-19, he started to experience generalized SPS symptomatology that steadily worsened the following 2-3 weeks, becoming unable to walk, requiring a walker, with significant thoracolumbar and bilateral leg stiffness and spasms. GAD ab were very high. After 3 monthly IVIg infusions he showed improvements, but his gait remains significantly stiff. All clinical changes, from baseline to post-Covid, and then post- IVIg have been video-documented. DISCUSSION: This is the first, clearly documented, severe GAD-positive SPS after COVID-19. Although viral or postviral causation can be incidental, the temporal connection with acute COVID-19, the severe disease worsening after symptom-onset, and the subsequent steady improvement after IVIg, suggest viral-triggered autoimmunity. Because COVID-19 reportedly can trigger or worsen GAD-associated diabetes type 1 through proinflammatory mediators, and SPS has been reportedly triggered by West Nile Virus, possibly through molecular mimicry, this case of acutely converting GAD-SLS to GAD-SPS suggest the need to explore viral etiologies in patients with GAD-SPS experiencing acute, long-lasting episodic exacerbations of stiffness and spasms

Repurposing MS Immunotherapies for CIDP and Other Autoimmune Neuropathies: Unfulfilled Promise or Efficient Strategy?

Despite advances in the treatment of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and other common autoimmune neuropathies (AN), still-many patients with these diseases do not respond satisfactorily to the available treatments. Repurposing of disease-modifying therapies (DMTs) from other autoimmune conditions, particularly multiple sclerosis (MS) and neuromyelitis optica spectrum disorders (NMOSD), is a promising strategy that may accelerate the establishment of novel treatment choices for AN. This approach appears attractive due to homologies in the pathogenesis of these diseases and the extensive post-marketing experience that has been gathered from treating MS and NMOSD patients. The idea is also strengthened by a number of studies that explored the efficacy of DMTs in animal models of AN but also in some CIDP patients. We here review the available preclinical and clinical data of approved MS therapeutics in terms of their applicability to AN, especially CIDP. Promising therapeutic approaches appear to be B cell-directed and complement-targeting strategies, such as anti-CD20/anti-CD19 agents, Bruton\u27s tyrosine kinase inhibitors and anti-C5 agents, as they exert their effects in the periphery. This is a major advantage because, in contrast to MS, their action in the periphery is sufficient to exert significant immunomodulation

Treatment for inclusion body myositis

Background Inclusion body myositis (IBM) is a late-onset inflammatory muscle disease (myopathy) associated with progressive proximal and distal limb muscle atrophy and weakness. Treatment options have attempted to target inflammatory and atrophic features of this condition (for example with immunosuppressive and immunomodulating drugs, anabolic steroids, and antioxidant treatments), although as yet there is no known effective treatment for reversing or minimising the progression of inclusion body myositis. In this review we have considered the benefits, adverse effects, and costs of treatment in targeting cardinal effects of the condition, namely muscle atrophy, weakness, and functional impairment. Objectives To assess the effects of treatment for IBM. Search methods On 7 October 2014 we search ed the Cochrane Neuromuscular Disease Group Specialized Register, the Cochrane Central Register for Controlled Trials (CENTRAL), MEDLINE, and EMBASE. Additionally in November 2014 we searched clinical trials registries for ongoing or completed but unpublished trials. Selection criteria We considered randomised or quasi-randomised trials, including cross-over trials, of treatment for IBM in adults compared to placebo or any other treatment for inclusion in the review. We specifically excluded people with familial IBM and hereditary inclusion body myopathy, but we included people who had connective tissue and autoimmune diseases associated with IBM, which may or may not be identified in trials. We did not include studies of exercise therapy or dysphagia management, which are topics of other Cochrane systematic reviews. Data collection and analysis We used standard Cochrane methodological procedures. Main results The review included 10 trials (249 participants) using different treatment regimens. Seven of the 10 trials assessed single agents, and 3 assessed combined agents. Many of the studies did not present adequate data for the reporting of the primary outcome of the review, which was the percentage change in muscle strength score at six months. Pooled data from two trials of interferon beta-1a (n = 58) identified no important difference in normalised manual muscle strength sum scores from baseline to six months (mean difference (MD) -0.06, 95% CI -0.15 to 0.03) between IFN beta-1a and placebo (moderate-quality evidence). A single trial of methotrexate (MTX) (n = 44) provided moderate-quality evidence that MTX did not arrest or slow disease progression, based on reported percentage change in manual muscle strength sum scores at 12 months. None of the fully published trials were adequately powered to detect a treatment effect. We assessed six of the nine fully published trials as providing very low-quality evidence in relation to the primary outcome measure. Three trials (n = 78) compared intravenous immunoglobulin (combined in one trial with prednisone) to a placebo, but we were unable to perform meta-analysis because of variations in study analysis and presentation of trial data, with no access to the primary data for re-analysis. Other comparisons were also reported in single trials. An open trial of anti-T lymphocyte immunoglobulin (ATG) combined with MTX versus MTX provided very low-quality evidence in favour of the combined therapy, based on percentage change in quantitative muscle strength sum scores at 12 months (MD 12.50%, 95% CI 2.43 to 22.57). Data from trials of oxandrolone versus placebo, azathioprine (AZA) combined with MTX versus MTX, and arimoclomol versus placebo did not allow us to report either normalised or percentage change in muscle strength sum scores. A complete analysis of the effects of arimoclomol is pending data publication. Studies of simvastatin and bimagrumab (BYM338) are ongoing. All analysed trials reported adverse events. Only 1 of the 10 trials interpreted these for statistical significance. None of the trials included prespecified criteria for significant adverse events. Authors\u27 conclusions Trials of interferon beta-1a and MTX provided moderate-quality evidence of having no effect on the progression of IBM. Overall trial design limitations including risk of bias, low numbers of participants, and short duration make it difficult to say whether or not any of the drug treatments included in this review were effective. An open trial of ATG combined with MTX versus MTX provided very low-quality evidence in favour of the combined therapy based on the percentage change data given. We were unable to draw conclusions from trials of IVIg, oxandrolone, and AZA plus MTX versus MTX. We need more randomised controlled trials that are larger, of longer duration, and that use fully validated, standardised, and responsive outcome measures