mononeuropathy and sensorimotor neuropathy, but never in patients with ganglionopathy, and reduced in patients with pronounced sensory symptoms. In the myopathies [40], varying degrees of inßammatory changes occur, in a perivascular, endomysial, or perimysial distribution. The majority of inÞltrating lymphocytes are T cells, and inßammatory cells in the perimysium are often associated with a vasculitis [41, 51]. Non-speciÞc abnormalities with degeneration, regeneration, muscle Þber size variation, split Þbers, atrophic Þbers, and ragged red Þbers are seen as well [41, 42].

There appears to be a complex Òvicious cycleÓ that involves humeral immunity described below (including anti-coagulants), innate immune factors such as CRP, complement activation and associated coagulopathy, and cytokine/ chemokine release that perpetuates the small vessel damage and leukocyte adherence.

Vasculopathy in the periphery and the CNS is characterized by a small-to-moderate perivascular accumulation of mononuclear cells, without destruction (e.g., Þbrinoid necrosis) of the blood vessel [43]. There may be small infarcts due to luminal occlusion. The pathogenic basis of vasculopathy remains largely unknown, but the pathologic Þndings have some similarities to the biopsies from diabetic patients [43]. Indeed, rheumatologists have a great deal to learn about the pathogenesis of SS from the glandular and extraglandular manifestations of diabetes [44].

The accessibility of the salivary gland to biopsy may provide a tissue model for understanding the underlying processes that originate with vascular changes and perivascular inÞltrates of mononuclear cells and dendritic cells. As outlined in the chapters on salivary gland pathology and neuroendocrine factors, analysis of the earliest vasculopathy changes in the SS gland may permit understanding of the molecular events that result in vasculopathy. These events include continued activation of the innate immune system that is reßected in type I interferon and interleukin-1 gene signatures found in SS salivary gland tissue biopsies [45] and the later homing of inßammatory cells

with resultant metalloproteinase and cytokine induction.

22.3.2The Role of Antibodies Associated with Neurological Manifestations of SS

The ÒpurestÓ example of humoral factors in neuropathogenesis involves anti-SSA antibodies in pregnant SS patients, where maternal antibodies cross the placenta to interfere with the developing fetal cardiac neural conducting system [46Ð48]. Another example of humoral-mediated neuropathic damage is the presence of anti-myelin-associated protein in SS patients with chronic inßammatory demyelinating polyneuropathy (CIDP). Anti-cardiolipin antibodies and lupus anti-coagulants predispose to thrombotic events including strokes and microvascular nephritis with hypertensive crises.

Among differences between SS and SLE, SS patients have a higher frequency than SLE patients of lymphoproliferative disorders including lymphoma. Accordingly, they have a higher frequency of antibodies associated with mixed cryoglobulinemia (i.e., monoclonal rheumatoid factors that participate in type II mixed cryoglobulin) and other paraneoplastic antibodies such as ANNA-1 or Ri [49, 50Ð53].

In these SS patients, the pathogenetic role of autoantibodies in neurological manifestations has been established.

Other autoantibodies have been associated with neurological symptoms but the association may not be causal.

SS patients, in comparison to SLE patients, have a higher frequency of autoantibodies to muscarinic receptors [54] and to fodrin, a structural brain antigen that has been found in circulation after stroke in non-autoimmune patients

[55].

These latter antibodies have been proposed to contribute to autonomic and central neurological manifestations, although it is unclear whether the antibodies are pathogenetic or the consequence of neurological damage.