Advances in the diagnosis, immunopathogenesis and therapies of IgM-anti-MAG antibody-mediated neuropathies.

Polyneuropathy with immunoglobulin M (IgM) monoclonal gammopathy is the most common paraproteinemic neuropathy, comprising a clinicopathologically and immunologically distinct entity. The clinical spectrum spans from distal paresthesias and mild gait imbalance to more severe sensory ataxia, with falls and a varying degree of distal sensorimotor deficits. In approximately 75% of patients, the monoclonal IgM immunoreacts with myelin-associated glycoprotein (MAG) and sulfoglucuronyl glycosphingolipid (SGPG), or other peripheral nerve glycolipids that serve as antigens. These antibodies are considered pathogenic because IgM and complement are deposited on the myelin sheath, splitting the myelin lamellae, while adoptive transfer of patients\u27 IgM into susceptible host animals causes sensory ataxia and reproduces the human pathology. In spite of the apparently convincing pathogenicity of these antibodies, the response to immunotherapies remains suboptimal. Clorambuscil, cladibrine, cyclophospamide and intravenous immunoglobulin may help some patients but the benefits are minimal and transient. Open-label studies in \u3e200 patients indicate that rituximab is helpful in 30-50% of these patients, even with long-term benefits, probably by suppressing IgM anti-MAG antibodies or inducing immunoregulatory T cells. Two controlled studies with rituximab did not however meet the primary endpoint, mostly because of the poor sensitivity of the scales used; they did however show statistical improvement in secondary endpoints and improved clinical functions in several patients. This review provides an overview of the clinical phenotypes and immunoreactivity of IgM to glycolipids or glycoproteins of peripheral nerve myelin, summarizes the progress on treatment with rituximab as a promising therapy, discusses the pitfalls of scales used, identifies possible biomarkers of response to therapy and highlights the promising new anti-B cell or target-specific immunotherapies

Neurological complications of immune checkpoint inhibitors: what happens when you \u27take the brakes off\u27 the immune system.

Patients with advanced malignancies treated with immune checkpoint inhibitors are at increased risk for developing immune-related neurological complications. It is a phenomenon of immunological twist when immunotherapy against co-stimulatory molecules activates previously normal T cells to kill tumor cells but, in so doing, the T cells become unrestrained, triggering other autoimmune diseases for which conventional immunotherapy is needed. The most common autoimmune neurological diseases, usually occurring within 2-12 weeks after immune checkpoint inhibitor initiation, include: inflammatory myopathies, myasthenia gravis, acute and chronic demyelinating polyradiculoneuropathies, vasculitic neuropathies, isolated cranial neuropathies, aseptic meningitis, autoimmune encephalitis, multiple sclerosis and hypophysitis. The neurological events can evolve rapidly, necessitating the need for vigilance at all stages of treatment, even after completion, because early immunotherapeutic interventions are effective. The review addresses these complications and the applied therapies, discusses immune pathomechanisms including triggering preexisting autoimmunity, highlights the distinction between paraneoplastic and autoimmune etiologies, and identifies uncertainties regarding risk factors, use of immune checkpoint inhibitors in patients with known immune diseases or restarting therapy after a neurological event. Although the autoimmune neurological complications are not very common, their incidence will likely increase as the use of immune checkpoint inhibitors in metastatic cancer is growing rapidly

Inflammatory Muscle Diseases.

INFLAMMATORY MYOPATHIES ARE THE LARGEST GROUP OF POTENTIALLY treatable myopathies in children and adults. They constitute a heterogeneous group of disorders that are best classified, on the basis of distinct clinicopathologic features, in four subtypes: dermatomyositis, polymyositis, necrotizing autoimmune myositis, and inclusion-body myositis (throughout this review, I use this term to refer specifically to sporadic inclusion-body myositis). 1-6 A fifth subtype, termed overlap myositis, is also beginning to be recognized. The identification of the correct subtype and the distinction of these conditions from other diseases that have characteristics that mimic these conditions is fundamental, because each subtype has a different prognosis and response to therapies. This review reflects the current knowledge of these conditions, highlights how best to avoid erroneous diagnoses, describes the main clinicopathologic and immunologic features, and provides practical guidelines regarding therapies

Progress in the therapy of myasthenia gravis: getting closer to effective targeted immunotherapies

PURPOSE OF REVIEW: To provide an update on immunomodulating and immunosuppressive therapies in myasthenia gravis and highlight newly approved, or pending approval, therapies with new biologics. RECENT FINDINGS: Preoperative IVIg is not needed to prevent myasthenic crisis in stable myasthenia gravis patients scheduled for surgery under general anesthesia, based on controlled data. Rituximab, if initiated early in new-onset myasthenia gravis, can lead to faster and more sustained remission even without immunotherapies in 35% of patients at 2 years. Biomarkers determining the timing for follow-up infusions in Rituximab-responding AChR-positive patients are discussed. Most patients with MuSK-positive myasthenia gravis treated with Rituximab have sustained long-term remission with persistent reduction of IgG4 anti-MuSK antibodies. Eculizumb in the extension REGAIN study showed sustained long-term pharmacological remissions and reduced exacerbations. Three new biologic agents showed promising results in phase-II controlled myasthenia gravis trials: Zilucoplan, a subcutaneous macrocyclic peptide inhibiting complement C5; Efgartigimod, an IgG1-derived Fc fragment binding to neonatal FcRn receptor; and Rozanolixizumab, a high-affinity anti-FcRn monoclonal antibody. Finally, the safety of ongoing myasthenia gravis immunotherapies during COVID19 pandemic is discussed. SUMMARY: New biologics against B cells, complement and FcRn receptor, are bringing us closer to successful targeted immunotherapies in the chronic management of myasthenia gravis promising an exciting future for antibody-mediated neurological diseases

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

IgG4-Mediated Neurologic Autoimmunities: Understanding the Pathogenicity of IgG4, Ineffectiveness of IVIg, and Long-Lasting Benefits of Anti-B Cell Therapies

Background and objectives: Describe the unique functions of immunoglobulin G4 (IgG4) in IgG4-neurologic disorders (IgG4-ND) and explain why, in contrast to their IgG1-counterparts, they respond poorly to intravenous immune globulin (IVIg) but effectively to anti-B cell therapies. Methods: The IgG4 structure and isotype switch, B cells and plasmablasts relevant to IgG4 production, and IgG4-induced disruption of the targeted antigens are reviewed and compared with IgG1-mediated autoimmune ND, where IVIg inhibits IgG1-triggered inflammatory effects. Results: The main IgG4-ND include muscle-specific kinase myasthenia; nodal/paranodal chronic inflammatory demyelinating polyradiculoneuropathy with antibodies to neurofascin-155, contactin-1/caspr-1, or pan-neurofascins; antileucine-rich, glioma-inactivated-1 and contactin-associated protein-like 2 associated-limbic encephalitis, Morvan syndrome, or neuromyotonia; and anti-IgLON5 disorder. The IgG4, because of its unique structural features in the hinge region, has noninflammatory properties being functionally monovalent and bispecific, unable to engage in cross-linking and internalization of the targeted antigen. In contrast to IgG1 subclass which is bivalent and monospecific, IgG4 does not activate complement and cannot bind to inhibitory Fcγ receptor (FcγRIIb) to activate cellular and complement-mediated immune responses, the key functions inhibited by IVIg. Because IVIg contains only 0.7%-2.6% IgG4, its idiotypes are of IgG1 subclass and cannot effectively neutralize IgG4 or sufficiently enhance IgG4 catabolism by saturating FcRn. In contrast, rituximab, by targeting memory B cells and IgG4-producing CD20-positive short-lived plasma cells, induces long-lasting clinical benefits. Discussion: Rituximab is the preferred treatment in IgG4-ND patients with severe disease by effectively targeting the production of pathogenic IgG-4 antibodies. In contrast, IVIG is ineffective because it inhibits immunoinflammatory functions irrelevant to the mechanistic effects of IgG4 and contains IgG-1 idiotypes that cannot sufficiently neutralize or possibly catabolize IgG4. Controlled studies with anti-CD19/20 monoclonals that also activate FcγRIIb may be more promising in treating IgG4-ND

Therapies in Stiff-Person Syndrome: Advances and Future Prospects Based on Disease Pathophysiology

Among the glutamic acid decarboxylase (GAD)-antibody-spectrum disorders, the most common phenotypic subset is the stiff-person syndrome (SPS), caused by impaired GABAergic inhibitory neurotransmission and autoimmunity characterized by very high titers of GAD antibodies and increased GAD-IgG intrathecal synthesis. If not properly treated or untreated because of delayed diagnosis, SPS progresses leading to disability; it is therefore fundamental to apply the best therapeutic schemes from the outset. This article is focused on the rationale of specific therapeutic strategies based on the SPS pathophysiology targeting both the impaired reciprocal GABAergic inhibition to symptomatically improve the main clinical manifestations of stiffness in the truncal and proximal limb muscles, gait dysfunction, and episodic painful muscle spasms and the autoimmunity to enhance improvement and slow down disease progression. A practical, step-by-step therapeutic approach is provided, highlighting the importance of combination therapies with the preferred gamma-aminobutyric acid-enhancing antispasmodic drugs, such as baclofen, tizanidine, benzodiazepines, and gabapentin, that provide the first-line symptomatic therapy, while detailing the application of current immunotherapies with intravenous immunoglobulin (IVIg) plasmapheresis, and rituximab. The pitfalls and concerns of long-term therapies in different age groups, including children, women planning pregnancy, and especially the elderly considering their comorbidities are emphasized, also highlighting the challenges in distinguishing the conditioning effects or expectations of chronically applied therapies from objective meaningful clinical benefits. Finally, the need for future targeted immunotherapeutic options based on disease immunopathogenesis and the biologic basis of autoimmune hyperexcitability are discussed, pointing out the unique challenges in the design of future controlled clinical trials especially in quantifying the extend and severity of stiffness, episodic or startle-triggered muscle spasms, task-specific phobias, and excitability

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

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