Immunotherapy considerations for distal sensory-predominant and small-fiber peripheral neuropathies

Increasing knowledge about the common widespread, distal-predominant polyneuropathies is shifting the standard of care beyond merely palliating symptom toward intervention. This is less advanced for the more prevalent but harder-to-ascertain distal sensory polyneuropathies (DSP) than for motor and demyelinating neuropathies. DSP comprises the sensory-predominant large-fiber axonal/demyelinating neuropathies plus the small-fiber sensory/autonomic axonopathies. Small-fiber disturbances can cause premature fatigue, neuropathic pain and itch, postural orthostasis tachycardia, and gastrointestinal distress. Diagnosis is difficult - screening for classic causes is mandatory but unproductive in a third to a half of patients (initially idiopathic DSP/iiDSP). Multiple large case series and two small passive-transfer studies suggest that autoimmunity may be a prevalent cause of iiDSP, particularly for small-fiber neuropathy. So, despite the knowledge gaps, immunotherapies effective for other neuropathies are increasingly considered for dysimmune iiDSP; particularly in otherwise healthy young patients with impaired life trajectories. To inform these difficult treatment decisions, this chapter summarizes diagnostic requirements for large- and small-fiber iiDSP and evaluates the type and strength of the evidence suggesting autoimmune causality in some. Concomitant rheumatologic conditions including often undiagnosed Sjögren's syndrome, predispose. Youth, abrupt onset, other organ dysimmunity, immune seromarkers, and prior responses to immunotherapy can provide additional evidence, but autoantibody panels are almost never useful. Uncontrolled studies suggest that apparently autoimmune DSP sometimes responds to corticosteroids, intravenous immunoglobulins, and plasmapheresis. However, these cannot be prescribed indiscriminately due to risk, cost/availability, and lack of controlled trials and guidelines. Enough preliminary data may have accrued to permit formulating initial consensus recommendations for selecting the subsets of patients in whom immunotherapy should or should not be considered. Patients, clinicians, and payors would benefit immediately, and highlighting priorities for research could promote long-term advances.