Small Fiber Neuropathy in Rheumatological Disorders

Patients with rheumatological disorders can present with a variety of syndromes that can result from Small Fiber Neuropathy (SFN). These include musculoskeletal pain,1 muscle cramps,2 fasciculations,3 widespread unexplained pain,4 reflex sympathetic dystrophy/complex regional pain syndrome,5 burning paresthesias, and autonomic instability including orthostatic hypotension, postural tachycardia, or gastrointestinal dysmotility.6,7

Several recent studies found that approximately 50% of fibromyalgia patients had reduced Epidermal Nerve Fiber Density (ENFD), consistent with SFN.1,8–12 In the study by Kosmidis et al. (2014), SFN was also found in patients with fibromyalgia and other concomitant rheumatologic disorders.

In Sjögren’s syndrome, Fauchais et al. reported that approximately 40% of patients experienced neuropathic pain with normal electrodiagnostic studies, due to SFN.13 Chai et al. reported that 80% of patients with Sjögren’s syndrome and neuropathy presented with burning feet, and 60% had symptoms in a multifocal or non-length dependent pattern.14 Sene et al. reported that patients with Sjögren’s syndrome associated neuropathy are characterized by older age at diagnosis and lower frequency of serum B-cell activation markers.15

In systemic lupus erythematosus (SLE), Oomatia et al. found that the prevalence of peripheral neuropathy in patients with SLE was 5.9%, with 17% exhibiting a painful SFN in a pattern consistent with dorsal root ganglionopathy and distal axonopathy.16 Birnbaum et al. also reported that SFN can occur in patients with rheumatoid arthritis as a complication of TNF-inhibitor therapy.17

SFN can also be associated with sarcoidosis,18,19 and has been implicated in the Gulf War veteran syndrome.20 Patients with Ehlers-Danlos hypermobility syndrome also have been reported to exhibit symptoms of neuropathic pain or autonomic instability.21–23

Making a diagnosis of SFN is important, as it enables the physician to explain the symptoms to their patients, direct testing for possible contributory causes, and decide on appropriate treatment. Bakkers et al. evaluated a total of 265 patients diagnosed with SFN, and found that it was associated with a severe impairment in quality of life.24 Schaefer et al., in a study of 100 patients, reported that SFN negatively impacts health status, function, and productivity and leads to substantial direct and indirect costs.25 Boruchow et al. examined the role of skin biopsy in the evaluation and management of patients with suspected SFN.26 A change in management or diagnosis occurred in 14 of 25 patients with definite SFN, 6 of 9 patients with borderline SFN, and 16 of 35 biopsy negative patients. They concluded that skin biopsy played a valuable role in the workup of these patients.

  1. Gemignani F. Fibromyalgia syndrome and small-fiber neuropathy. Ann Neurol. 2014;76(6):916. [PubMed]
  1. Lopate G, Streif E, Harms M, Weihl C, Pestronk A. Cramps and small-fiber neuropathy. Muscle Nerve. 2013;48(2):252-255. [PubMed]
  1. Tzatha E, Chin R. Small fiber abnormalities in skin biopsies of patients with benign fasciculations. J Clin Neuromuscul Dis. 2014;16(1):12-14. [PubMed]
  1. Oaklander A, Klein M. Evidence of small-fiber polyneuropathy in unexplained, juvenile-onset, widespread pain syndromes. Pediatrics. 2013;131(4):e1091-100. [PubMed]
  1. Oaklander A, Fields H. Is reflex sympathetic dystrophy/complex regional pain syndrome type I a small-fiber neuropathy? Ann Neurol. 2009;65(6):629-638. [PubMed]
  1. Gibbons C. Small fiber neuropathies. Continuum (Minneap Minn). 2014;20(5 Peripheral Nervous System Disorders):1398-1412. [PubMed]
  1. Haensch C, Tosch M, Katona I, Weis J, Isenmann S. Small-fiber neuropathy with cardiac denervation in postural tachycardia syndrome. Muscle Nerve. 2014;50(6):956-961. [PubMed]
  1. Caro X, Winter E. Evidence of abnormal epidermal nerve fiber density in fibromyalgia: clinical and immunologic implications. Arthritis Rheumatol. 2014;66(7):1945-1954. [PubMed]
  1. Giannoccaro M, Donadio V, Incensi A, Avoni P, Liguori R. Small nerve fiber involvement in patients referred for fibromyalgia. Muscle Nerve. 2014;49(5):757-759. [PubMed]
  1. Kosmidis M, Koutsogeorgopoulou L, Alexopoulos H, et al. Reduction of Intraepidermal Nerve Fiber Density (IENFD) in the skin biopsies of patients with fibromyalgia: a controlled study. J Neurol Sci. 2014;347(1-2):143-147. [PubMed]
  1. Oaklander A, Herzog Z, Downs H, Klein M. Objective evidence that small-fiber polyneuropathy underlies some illnesses currently labeled as fibromyalgia. Pain. 2013;154(11):2310-2316. [PubMed]
  1. Üçeyler N, Zeller D, Kahn A, et al. Small fibre pathology in patients with fibromyalgia syndrome. Brain. 2013;136(Pt 6):1857-1867. [PubMed]
  1. Fauchais A, Richard L, Gondran G, et al. [Small fibre neuropathy in primary Sjögren syndrome]. Rev Med Interne. 2011;32(3):142-148. [PubMed]
  1. Chai J, Herrmann D, Stanton M, Barbano R, Logigian E. Painful small-fiber neuropathy in Sjogren syndrome. Neurology. 2005;65(6):925-927. [PubMed]
  1. Sène D, Cacoub P, Authier F, et al. Sjögren Syndrome-Associated Small Fiber Neuropathy: Characterization From a Prospective Series of 40 Cases. Medicine (Baltimore). 2013;92(5):e10-e18. [PubMed]
  1. Oomatia A, Fang H, Petri M, Birnbaum J. Peripheral neuropathies in systemic lupus erythematosus: clinical features, disease associations, and immunologic characteristics evaluated over a twenty-five-year study period. Arthritis Rheumatol. 2014;66(4):1000-1009. [PubMed]
  1. Birnbaum J, Bingham C. 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. Semin Arthritis Rheum. 2013;43(5):638-647. [PMC]
  1. Bakkers M, Faber C, Drent M, et al. Pain and autonomic dysfunction in patients with sarcoidosis and small fibre neuropathy. J Neurol. 2010;257(12):2086-2090. [PMC]
  1. Hoitsma E, Marziniak M, Faber C, et al. Small fibre neuropathy in sarcoidosis. The Lancet. 359(9323):2085-2086. doi:1016/S0140-6736(02)08912-2
  1. Li M, Xu C, Yao W, et al. Self-reported post-exertional fatigue in Gulf War veterans: roles of autonomic testing. Front Neurosci. 2014;7:269. [PMC]
  1. Camerota F, Celletti C, Castori M, Grammatico P, Padua L. Neuropathic pain is a common feature in Ehlers-Danlos syndrome. J Pain Symptom Manage. 2011;41(1):e2-4. [PubMed]
  1. Voermans N, Knoop H, Bleijenberg G, van E. Fatigue is associated with muscle weakness in Ehlers-Danlos syndrome: an explorative study. Physiotherapy. 2011;97(2):170-174. [PubMed]
  1. De W, Rombaut L, Leybaert L, et al. Dysautonomia and its underlying mechanisms in the hypermobility type of Ehlers-Danlos syndrome. Semin Arthritis Rheum. 2014;44(1):93-100. [PubMed]
  1. Bakkers M, Faber C, Hoeijmakers J, Lauria G, Merkies I. Small fibers, large impact: quality of life in small-fiber neuropathy. Muscle Nerve. 2014;49(3):329-336. [PubMed]
  1. Schaefer C, Mann R, Sadosky A, et al. Burden of Illness Associated with Peripheral and Central Neuropathic Pain among Adults Seeking Treatment in the United States: A Patient-Centered Evaluation. Pain Med. 2014;15(12):2105-2119. [PMC]
  1. Boruchow S, Gibbons C. Utility of skin biopsy in management of small fiber neuropathy. Muscle Nerve. 2013;48(6):877-882. [PubMed]

Related Articles

Small Fiber Neuropathy in Rheumatological Disorders

Patients with rheumatological disorders can present with a variety of syndromes that can result from Small Fiber Neuropathy (SFN). These include musculoskeletal pain,1 muscle cramps,2 fasciculations,3 widespread unexplained pain,4 reflex sympathetic dystrophy/complex regional pain syndrome,5 burning paresthesias, and autonomic instability including orthostatic hypotension, postural tachycardia, or gastrointestinal dysmotility.6,7

Several recent studies found that approximately 50% of fibromyalgia patients had reduced Epidermal Nerve Fiber Density (ENFD), consistent with SFN.1,8–12 In the study by Kosmidis et al. (2014), SFN was also found in patients with fibromyalgia and other concomitant rheumatologic disorders.

In Sjögren’s syndrome, Fauchais et al. reported that approximately 40% of patients experienced neuropathic pain with normal electrodiagnostic studies, due to SFN.13 Chai et al. reported that 80% of patients with Sjögren’s syndrome and neuropathy presented with burning feet, and 60% had symptoms in a multifocal or non-length dependent pattern.14 Sene et al. reported that patients with Sjögren’s syndrome associated neuropathy are characterized by older age at diagnosis and lower frequency of serum B-cell activation markers.15

In systemic lupus erythematosus (SLE), Oomatia et al. found that the prevalence of peripheral neuropathy in patients with SLE was 5.9%, with 17% exhibiting a painful SFN in a pattern consistent with dorsal root ganglionopathy and distal axonopathy.16 Birnbaum et al. also reported that SFN can occur in patients with rheumatoid arthritis as a complication of TNF-inhibitor therapy.17

SFN can also be associated with sarcoidosis,18,19 and has been implicated in the Gulf War veteran syndrome.20 Patients with Ehlers-Danlos hypermobility syndrome also have been reported to exhibit symptoms of neuropathic pain or autonomic instability.21–23

Making a diagnosis of SFN is important, as it enables the physician to explain the symptoms to their patients, direct testing for possible contributory causes, and decide on appropriate treatment. Bakkers et al. evaluated a total of 265 patients diagnosed with SFN, and found that it was associated with a severe impairment in quality of life.24 Schaefer et al., in a study of 100 patients, reported that SFN negatively impacts health status, function, and productivity and leads to substantial direct and indirect costs.25 Boruchow et al. examined the role of skin biopsy in the evaluation and management of patients with suspected SFN.26 A change in management or diagnosis occurred in 14 of 25 patients with definite SFN, 6 of 9 patients with borderline SFN, and 16 of 35 biopsy negative patients. They concluded that skin biopsy played a valuable role in the workup of these patients.

  1. Gemignani F. Fibromyalgia syndrome and small-fiber neuropathy. Ann Neurol. 2014;76(6):916.[PubMed]
  1. Lopate G, Streif E, Harms M, Weihl C, Pestronk A. Cramps and small-fiber neuropathy. Muscle Nerve. 2013;48(2):252-255.[PubMed]
  1. Tzatha E, Chin R. Small fiber abnormalities in skin biopsies of patients with benign fasciculations. J Clin Neuromuscul Dis. 2014;16(1):12-14.[PubMed]
  1. Oaklander A, Klein M. Evidence of small-fiber polyneuropathy in unexplained, juvenile-onset, widespread pain syndromes. Pediatrics. 2013;131(4):e1091-100.[PubMed]
  1. Oaklander A, Fields H. Is reflex sympathetic dystrophy/complex regional pain syndrome type I a small-fiber neuropathy? Ann Neurol. 2009;65(6):629-638.[PubMed]
  1. Gibbons C. Small fiber neuropathies. Continuum (Minneap Minn). 2014;20(5 Peripheral Nervous System Disorders):1398-1412.[PubMed]
  1. Haensch C, Tosch M, Katona I, Weis J, Isenmann S. Small-fiber neuropathy with cardiac denervation in postural tachycardia syndrome. Muscle Nerve. 2014;50(6):956-961.[PubMed]
  1. Caro X, Winter E. Evidence of abnormal epidermal nerve fiber density in fibromyalgia: clinical and immunologic implications. Arthritis Rheumatol. 2014;66(7):1945-1954.[PubMed]
  1. Giannoccaro M, Donadio V, Incensi A, Avoni P, Liguori R. Small nerve fiber involvement in patients referred for fibromyalgia. Muscle Nerve. 2014;49(5):757-759.[PubMed]
  1. Kosmidis M, Koutsogeorgopoulou L, Alexopoulos H, et al. Reduction of Intraepidermal Nerve Fiber Density (IENFD) in the skin biopsies of patients with fibromyalgia: a controlled study. J Neurol Sci. 2014;347(1-2):143-147.[PubMed]
  1. Oaklander A, Herzog Z, Downs H, Klein M. Objective evidence that small-fiber polyneuropathy underlies some illnesses currently labeled as fibromyalgia. Pain. 2013;154(11):2310-2316.[PubMed]
  1. Üçeyler N, Zeller D, Kahn A, et al. Small fibre pathology in patients with fibromyalgia syndrome. Brain. 2013;136(Pt 6):1857-1867.[PubMed]
  1. Fauchais A, Richard L, Gondran G, et al. [Small fibre neuropathy in primary Sjögren syndrome]. Rev Med Interne. 2011;32(3):142-148.[PubMed]
  1. Chai J, Herrmann D, Stanton M, Barbano R, Logigian E. Painful small-fiber neuropathy in Sjogren syndrome. Neurology. 2005;65(6):925-927.[PubMed]
  1. Sène D, Cacoub P, Authier F, et al. Sjögren Syndrome-Associated Small Fiber Neuropathy: Characterization From a Prospective Series of 40 Cases. Medicine (Baltimore). 2013;92(5):e10-e18.[PubMed]
  1. Oomatia A, Fang H, Petri M, Birnbaum J. Peripheral neuropathies in systemic lupus erythematosus: clinical features, disease associations, and immunologic characteristics evaluated over a twenty-five-year study period. Arthritis Rheumatol. 2014;66(4):1000-1009.[PubMed]
  1. Birnbaum J, Bingham C. 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. Semin Arthritis Rheum. 2013;43(5):638-647.[PMC]
  1. Bakkers M, Faber C, Drent M, et al. Pain and autonomic dysfunction in patients with sarcoidosis and small fibre neuropathy. J Neurol. 2010;257(12):2086-2090.[PMC]
  1. Hoitsma E, Marziniak M, Faber C, et al. Small fibre neuropathy in sarcoidosis. The Lancet. 359(9323):2085-2086.
    doi:
    1016/S0140-6736(02)08912-2
  1. Li M, Xu C, Yao W, et al. Self-reported post-exertional fatigue in Gulf War veterans: roles of autonomic testing. Front Neurosci. 2014;7:269.[PMC]
  1. Camerota F, Celletti C, Castori M, Grammatico P, Padua L. Neuropathic pain is a common feature in Ehlers-Danlos syndrome. J Pain Symptom Manage. 2011;41(1):e2-4.[PubMed]
  1. Voermans N, Knoop H, Bleijenberg G, van E. Fatigue is associated with muscle weakness in Ehlers-Danlos syndrome: an explorative study. Physiotherapy. 2011;97(2):170-174.[PubMed]
  1. De W, Rombaut L, Leybaert L, et al. Dysautonomia and its underlying mechanisms in the hypermobility type of Ehlers-Danlos syndrome. Semin Arthritis Rheum. 2014;44(1):93-100.[PubMed]
  1. Bakkers M, Faber C, Hoeijmakers J, Lauria G, Merkies I. Small fibers, large impact: quality of life in small-fiber neuropathy. Muscle Nerve. 2014;49(3):329-336.[PubMed]
  1. Schaefer C, Mann R, Sadosky A, et al. Burden of Illness Associated with Peripheral and Central Neuropathic Pain among Adults Seeking Treatment in the United States: A Patient-Centered Evaluation. Pain Med. 2014;15(12):2105-2119.[PMC]
  1. Boruchow S, Gibbons C. Utility of skin biopsy in management of small fiber neuropathy. Muscle Nerve. 2013;48(6):877-882.[PubMed]

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