Small fiber neuropathy (SFN) affects over one-third of patients with systemic sarcoidosis and causes pain and sensory changes that affect quality of life.  While large fiber neuropathy in sarcoidosis is granulomatous in nature, the underlying pathophysiology of sarcoidosis-associated SFN (SSFN) remains unknown but is thought to be immune-mediated through circulating and local cytokines in the skin where small nerve fiber endings terminate.

This prospective study included 59 patients (17 male) with small fiber neuropathy, 31 with biopsy-confirmed systemic sarcoidosis and 28 with non-sarcoidosis etiologies (e.g., diabetes, Sjogrens syndrome, COVID infection or idiopathic disease). All patients were clinically evaluated and underwent punch skin biopsy at the distal leg and thigh for determination of intraepidermal nerve fiber density. Immunohistochemical staining of affected skin was performed for interleukin (IL)-1, IL-2, IL-6, IL-8, transformative growth factor-β1 (TGF-β1) and tumor necrosis factor-alpha (TNF-a).    

All patients had pain and paresthesias. Abnormal skin biopsies were observed  in 71% (22/31) of patients with SSFN and 36% (10/28) of patients with SFN due to other causes (NSFN). Increased immunostaining of interleukin-2 and TNF-a was present in both groups but increased TGF-β1 staining was more frequently seen in patients with SSFN (58% of patients) compared to NSFN (29% of patients) (p=.035).    

TGF-β1, a cytokine central to granuloma formation, extracellular matrix remodeling, and neural repair, was significantly elevated in the skin of sarcoidosis-associated SFN compared with other etiologies. These findings suggest that SSFN may reflect a distinct pathophysiologic process involving both granulomatous inflammation and local neuroinflammatory or regenerative mechanisms at the level of small nerve fibers. Although further studies are needed, these findings suggest that TGF-β1 may serve as a potential disease-specific biomarker for SSFN.