ARA 290 Improves Symptoms in Patients with Sarcoidosis-Associated Small Nerve Fiber Loss and Increases Corneal Nerve Fiber Density

Albert Dahan,Martijn R Tannemaat,Anthony Cerami,Monique Van Velzen,Oscar Vogels,Paolo L Proto,Ann Dunne,Lara Heij,Maarten Swartjes,Elise Sarton,Michael Brines,Marieke Niesters

doi:10.2119/molmed.2013.00122

Albert Dahan, Martijn R Tannemaat + Show 10 more

Open Access

https://doi.org/10.2119/molmed.2013.00122

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Abstract

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.

Highlights

Sarcoidosis is an immune-mediated, inflammatory orphan disease of unclear etiology that can affect virtually any organ of the body [1]
Rationale for Dose Selection Results of a previous study performed in sarcoidosis patients with painful small-fiber neuropathy showed that 2 mg ARA 290 administered intravenously (IV) three times weekly improved neuropathic symptoms
Sarcoidosis complicated by small-fiber neuropathy is a chronic disease characterized by the loss of small nerve fibers with associated pain, decreased temperature sensitivity, thermal allodynia and pronounced autonomic dysfunction that severely degrades quality of life

Summary

Introduction

Sarcoidosis is an immune-mediated, inflammatory orphan disease of unclear etiology that can affect virtually any organ of the body [1]. In about one-third of patients, sarcoidosis evolves into a chronic, progressive disease [2]. In these refractory cases, therapy has generally consisted of immune suppression, which has been associated with a variable response rate [3]. It has become apparent that a significant proportion of patients with chronic sarcoidosis report symptoms that suggest abnormal function of the small nerve fibers of the sensory and autonomic nervous systems [4,5,6,7,8]. Patients having reduced nerve fiber densities typically complain of pain, numbness and/or dysesthesia, as well as autonomic symptoms that can be extremely variable depending on the organ affected [5]. The neuropathic symptoms in these patients are frequently severe and are major contributors to the poor quality of life of those afflicted [10]

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