Non-length-dependent and length-dependent small-fiber neuropathies associated with tumor necrosis factor (TNF)-inhibitor therapy in patients with rheumatoid arthritis: expanding the spectrum of neurological disease associated with TNF-inhibitors

Abstract

Objective: Small-fiber neuropathy causes severe burning pain, requires diagnostic approaches such as skin biopsy, and encompasses two subtypes based on distribution of neuropathic pain. Such biopsy-proven subtypes of small-fiber neuropathies have not been previously described as complications of tumor necrosis factor (TNF)-inhibitor therapy.

Methods: We therefore characterized clinical and skin biopsy findings in three rheumatoid arthritis (RA) patients who developed small-fiber neuropathies associated with TNF-inhibitors. We also conducted a systematic review of the literature to characterize subtypes of neuropathies previously reported in association with TNF-inhibitor therapy.

Results: Two patients presented with a "non-length-dependent" small-fiber neuropathy, experiencing unorthodox patterns of burning pain affecting the face, torso, and proximal extremities. Abnormal skin biopsy findings were limited to the proximal thigh, which is a marker of proximal-most dorsal root ganglia degeneration. In contrast, one patient presented with a "length-dependent" small-fiber neuropathy, experiencing burning pain only in the feet. Abnormal skin biopsy findings were limited to the distal feet, which is a marker of distal-most axonal degeneration. One patient developed a small-fiber neuropathy in the context of TNF-inhibitor-induced lupus. In all patients, neuropathies occurred during TNF-inhibitor-induced remission of RA disease activity and improved on withdrawal of TNF-inhibitors.

Conclusions: We describe a spectrum of small-fiber neuropathies not previously reported in association with TNF-inhibitor therapy, with clinical and skin biopsy findings suggestive of dorsal root ganglia as well as axonal degeneration. The development of small-fiber neuropathies during inactive joint disease and improvement of neuropathic pain upon withdrawal of TNF-inhibitor suggest a causative role of TNF-inhibitors.

Fig. 1

PRISMA statement for identification of TNF-inhibitor-associated neuropathies used in PUBMED. As described in the text, no further articles were identified using the other specified search engines.

Fig. 2

Skin biopsies distinguishing between length-dependent versus non-length-dependent small-fiber neuropathies in patients treated with TNF-inhibitor therapy. (A) and (B) illustrate the skin biopsy obtained from patient 1 with a length-dependent, small-fiber neuropathy. In contrast (C) and (D) illustrate the skin biopsy taken from patient 3 with a non-length-dependent, small-fiber neuropathy. The arrowheads demarcate the epidermal–dermal border, and the arrows indicate unmyelinated nerves that are immunostained against the panaxonal marker PGP 9.5. The top row refers to skin biopsy sites taken from the proximal thigh, and the bottom row refers to biopsy sites from the distal leg. In patient 1 with a length-dependent small-fiber neuropathy, there is decreased intra-epidermal nerve fiber density in the distal leg (Fig. 2B), compared to the proximal thigh (Fig. 2A). In contrast, in patient with a non-length-dependent small-fiber neuropathy, there is the opposing pattern with virtual absence of unmyelinated nerves in the proximal thigh (Fig. 2C), but with normal intra-epidermal nerve-fiber density in the distal leg (Fig. 2D).