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

Abstract

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’ 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 >200 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.

Peripheral nervous system involvement in lymphomas

“…In anti-MAG antibody neuropathies, evidence from trials of immunotherapies is inadequate to recommend any particular treatment. 29 However, data from approximately 200 patients treated in the last 15 years show that rituximab helped 30% to 50% of the patients, 30 with WM showing the same rate of response as patients with IgM MGUS. 31 Therapeutic option should therefore consider rituximab, as a cornerstone of the therapy, in combination with chemotherapy such as bendamustine or cyclophosphamide, as from WM guidelines.…”

Diagnosis and management of sensory polyneuropathy

“…Patients who have an identical clinical and electrophysiologic phenotype but lack MAG antibodies can be classified as having DADS-CIDP36127; such patients may carry a better prognosis and respond more favorably to intravenous immunoglobulins, corticosteroids, and plasma exchange 127. The clinical hallmark of DADS neuropathy is the gradual onset of sensory ataxia resulting from impaired proprioception 128. Weakness is less prominent and, when present, affects the distal lower extremities 129.…”

“…Although cytotoxic agents such as fludarabine, cyclophosphamide, and chlorambucil may be beneficial, their toxicities limit longterm use 212. Rituximab, a monoclonal antibody that targets CD20 (a B cell surface antigen) and depletes circulating B cells, has been used with success in 30-50% of patients in uncontrolled trials 128225. The primary endpoints in two placebo controlled randomized trials of rituximab failed to reach statistical significance, although secondary endpoints such as time-to-walk scales significantly improved 225226227.…”

Boundaries of chronic inflammatory demyelinating polyradiculoneuropathy

“…In the EFNS/PNS guideline, the polyneuropathy associated with IgM paraproteins carrying anti‐MAG reactivity was separated from the rest of CIDP as the clinical course appeared different, it is a length‐dependent neuropathy, and it is poorly responsive to immune therapy, including corticosteroids, IVIG and plasma exchange . Anti‐MAG neuropathy is a chronic, slowly progressive disorder affecting mainly older patients with distal, predominantly sensory symptoms and signs, often with tremor and ataxia . The anti‐MAG and anti‐SGPG antibodies are considered pathogenic because IgM and complement are deposited on the myelin sheath, leading to myelin widening between adjacent loops of paranodal myelin (widely spaced myelin) without evidence of inflammation, although intraneural injections with human anti‐MAG antibodies in animals revealed inflammatory, macrophage‐mediated demyelination .…”

“…12,13 Anti-MAG neuropathy is a chronic, slowly progressive disorder affecting mainly older patients with distal, predominantly sensory symptoms and signs, often with tremor and ataxia. 14,15 The anti-MAG and anti-SGPG antibodies are considered pathogenic because IgM and complement are deposited on the myelin sheath, leading to myelin widening between adjacent loops of paranodal myelin (widely spaced myelin) without evidence of inflammation, 16 although intraneural injections with human anti-MAG antibodies in animals revealed inflammatory, macrophage-mediated demyelination. 17,18 Moreover, immunization of cats with SGPG induced anti-SGPG antibodies and sensory neuronopathy clinically resembling the sensory ataxia of patients with IgM anti-MAG/SGPG neuropathy.…”