ARA 290 Improves Symptoms in Patients with Sarcoidosis-Associated Small Nerve Fiber Loss and Increases Corneal Nerve Fiber Density
Small nerve fiber loss and damage (SNFLD) is a frequent complication of sarcoidosis that is associated with autonomic dysfunction and sensory abnormalities, including pain syndromes that severely degrade the quality of life. SNFLD is hypothesized to arise from the effects of immune dysregulation, an essential feature of sarcoidosis, on the peripheral and central nervous systems. Current therapy of sarcoidosis-associated SNFLD consists primarily of immune suppression and symptomatic treatment; however, this treatment is typically unsatisfactory. ARA 290 is a small peptide engineered to activate the innate repair receptor that antagonizes inflammatory processes and stimulates tissue repair. Here we show in a blinded, placebo-controlled trial that 28 d of daily subcutaneous administration of ARA 290 in a group of patients with documented SNFLD significantly improves neuropathic symptoms. In addition to improved patient-reported symptom-based outcomes, ARA 290 administration was also associated with a significant increase in corneal small nerve fiber density, changes in cutaneous temperature sensitivity, and an increased exercise capacity as assessed by the 6-minute walk test. On the basis of these results and of prior studies, ARA 290 is a potential disease-modifying agent for treatment of sarcoidosis-associated SNFLD.
This work was supported in part by a grant from the Dutch government to the Netherlands Institute for Regenerative Medicine (NIRM, grant FES0908). Joop van Heerikhuize, Department of Image Analysis of the Netherlands Institute for Neuroscience, provided crucial support by developing the macro used for automated quantification of the CCM images. The authors thank the patients and their families for agreeing to participate in this trial. We also wish to recognize M Drent and E Hoitsma for their pioneering work identifying the existence of small-fiber neuropathy and its major negative impact on quality of life in patients with sarcoidosis and for their invaluable input. We also thank L Aarts, R Baughman, F Breedveld, D Culver, G Lauria, R Kirk, N Lois, R Malik, A Rabelink and M Yamin for their support, assistance and helpful advice that made this study possible.
- 25.Lauria G, et al. (2010) European Federation of Neurological Societies/Peripheral Nerve Society Guideline on the use of skin biopsy in the diagnosis of small fiber neuropathy. Report of a joint task force of the European Federation of Neurological Societies and the Peripheral Nerve Society. Eur. J. Neurol. 17:903–12, e44–9.CrossRefPubMedGoogle Scholar
- 28.Tavakoli M, Malik RA. (2011) Corneal confocal microscopy: a novel non-invasive technique to quantify small fibre pathology in peripheral neuropathies. J. Vis. Exp. January 3:pii: 2194.Google Scholar
- 31.ATS statement. (2002) Guidelines for the six-minute walk test. Am. J. Respir. Crit. Care Med. 166:111–7.Google Scholar
- 42.Gremeaux V, et al. (2011) Determining the minimal clinically important difference for the six-minute walk test and the 200-meter fast-walk test during cardiac rehabilitation program in coronary artery disease patients after acute coronary syndrome. Arch. Phys. Med. Rehabil. 92:611–9.CrossRefPubMedGoogle Scholar
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