Biopsy-Proven Small-Fiber Neuropathy in Primary Sjögren's Syndrome: Neuropathic Pain Characteristics, Autoantibody Findings, and Histopathologic Features

Abstract

Objective: Painful small-fiber neuropathies (SFNs) in primary Sjögren's syndrome (SS) may present as pure or mixed with concurrent large-fiber involvement. SFN can be diagnosed by punch skin biopsy results that identify decreased intra-epidermal nerve-fiber density (IENFD) of unmyelinated nerves.

Methods: We compared 23 consecutively evaluated patients with SS with pure and mixed SFN versus 98 patients without SFN. We distinguished between markers of dorsal root ganglia (DRG) degeneration (decreased IENFD in the proximal thigh versus the distal leg) versus axonal degeneration (decreased IENFD in the distal leg versus the proximal thigh).

Results: There were no differences in pain intensity, pain quality, and treatment characteristics in the comparison of 13 patients with pure SFN versus 10 patients with mixed SFN. Ten patients with SFN (approximately 45%) had neuropathic pain preceding sicca symptoms. Opioid analgesics were prescribed to approximately 45% of patients with SFN. When compared to 98 patients without SFN, the 23 patients with SFN had an increased frequency of male sex (30% versus 9%; P < 0.01), a decreased frequency of anti-Ro 52 (P = 0.01) and anti-Ro 60 antibodies (P = 0.01), rheumatoid factor positivity (P < 0.01), and polyclonal gammopathy (P < 0.01). Eleven patients had stocking-and-glove pain, and 12 patients had nonstocking-and-glove pain. Skin biopsy results disclosed patterns of axonal (16 patients) and DRG injury (7 patients).

Conclusion: SS SFN had an increased frequency among male patients, a decreased frequency of multiple antibodies, frequent treatment with opioid analgesics, and the presence of nonstocking-and-glove pain. Distinguishing between DRG versus axonal injury is significant, especially given that mechanisms targeting the DRG may result in irreversible neuronal cell death. Altogether, these findings highlight clinical, autoantibody, and pathologic features that can help to define mechanisms and treatment strategies.

Figure 1.

Distribution of neuropathic pain in patients with abnormal skin biopsy results. A, 11 patients presented with a stocking-and-glove pattern of neuropathic pain, frequently referred to as a length-dependent pattern of pain. In this pattern, the clinical site of injury may be suspected to reflect axonal (Ax) damage. In 10 of these 11 patients, the skin biopsy results similarly showed patterns of axonal injury. B, Twelve patients described a contrasting pattern of neuropathic pain termed nonlength-dependent pain distribution, occurring in a proximal, patchy, and/or asymmetric pattern. In this pattern, the clinical site of injury may be suspected to reflect dorsal root ganglia (DRG) injury. In 6 of 12 patients, skin biopsy results showed findings of DRG degeneration. In contrast, the remaining 6 of the 12 patients with nonlength-dependent pain had biopsy results suggestive of axonal injury. Co-occurring peripheral nerve syndromes: * = sensory neuropathy; ** = axonal sensorimotor (SM) polyneuropathy; *** = asymmetric axonal SM polyneuropathy; **** = axonal sensory neuropathy.

Figure 2.

Skin biopsy specimens associated with patterns of neuropathic pain. Arrows indicate unmyelinated nerves immunostained against the panaxonal marker PGP 9.5. Skin biopsy specimens taken from the proximal thigh (A) and distal leg (B) in a patient with a length-dependent pattern of neuropathic pain. Decreased intra-epidermal nerve-fiber density (IENFD) was noted in the distal leg versus the proximal thigh, consistent with a pattern of axonal degeneration. Skin biopsy specimens taken from the proximal thigh (C) and distal leg (D) in a patient with a nonlength-dependent pattern of neuropathic pain. Decreased IENFD was noted in the proximal thigh versus the distal leg, consistent with a pattern of dorsal root ganglia degeneration.