Molecular Medicine

, Volume 18, Issue 11, pp 1430–1436 | Cite as

Safety and Efficacy of ARA 290 in Sarcoidosis Patients with Symptoms of Small Fiber Neuropathy: A Randomized, Double-Blind Pilot Study

  • Lara Heij
  • Marieke Niesters
  • Maarten Swartjes
  • Elske Hoitsma
  • Marjolein Drent
  • Ann Dunne
  • Jan C. Grutters
  • Oscar Vogels
  • Michael Brines
  • Anthony Cerami
  • Albert Dahan
Research Article


ARA 290 (a peptide designed to activate the innate repair receptor that arrests injury and initiates cytoprotection, antiinflammation and healing) reduces allodynia in preclinical neuropathy models. We studied the safety and efficacy of ARA 290 to reduce symptoms of small fiber neuropathy (SFN) in patients with sarcoidosis. A total of 22 patients diagnosed with sarcoidosis and symptoms of SFN were enrolled in a double-blind, placebo-controlled exploratory trial consisting of three times weekly intravenous dosing of ARA 290 (2 mg; n = 12) or placebo (n = 10) for 4 wks. Inclusion criteria were a diagnosis of neuropathy and a spontaneous pain score of ≥5 (Brief Pain Inventory [BPI]). Endpoints assessed were changes in pain intensity and the small fiber neuropathy screening list (SFNSL) score, quality of life (SF-36), depressive symptoms (Inventory of Depressive Symptomatology [IDS]) and fatigue (Fatigue Assessment Scale [FAS]). No safety concerns were raised by clinical or laboratory assessments. The ARA 290 group showed significant (p < 0.05) improvement at wk 4 in SFNSL score compared with placebo (Δ −11.5 ± 3.04 versus Δ −2.9 ± 3.34 [standard error of the mean]). Additionally, the ARA 290 group showed a significant change from baseline in the pain and physical functioning dimensions of the SF-36 (Δ −23.4 ± 5.5 and Δ −14.6 ± 3.9, respectively). The mean BPI and FAS scores improved significantly but equivalently in both patient groups. No change was observed in the IDS. ARA 290 appears to be safe in patients with sarcoidosis and can reduce neuropathic symptoms.



The authors thank patients, and their families as well as F Breedveld, A Rabelink, L Aarts, E Lansink and E Sarton for support and assistance in making this study possible. This was an investigator-initiated study. ARA 290 was supplied by Araim Pharmaceuticals.


  1. 1.
    Chai J, Herrmann DN, Stanton M, Barbano RL, Logigian EL. (2005) Painful small-fiber neuropathy in Sjogren syndrome. Neurology. 65:925–7.CrossRefGoogle Scholar
  2. 2.
    Tavee J, Culver D. (2011) Sarcoidosis and small-fiber neuropathy. Curr. Pain Headache Rep. 15:201–6.CrossRefGoogle Scholar
  3. 3.
    Burns TM, Dyck PJ, Aksamit AJ. (2006) The natural history and long-term outcome of 57 limb sarcoidosis neuropathy cases. J. Neurol. Sci. 244:77–87.CrossRefGoogle Scholar
  4. 4.
    Hoitsma E, De Vries J, Drent M. (2011) The small fiber neuropathy screening list: construction and cross-validation in sarcoidosis. Respir. Med. 105:95–100.CrossRefGoogle Scholar
  5. 5.
    Lower EE, Weiss KL. (2008) Neurosarcoidosis. Clin. Chest Med. 29:475–92, ix.CrossRefGoogle Scholar
  6. 6.
    Bakkers M, et al. (2009) Intraepidermal nerve fiber density and its application in sarcoidosis. Neurology. 73:1142–8.CrossRefGoogle Scholar
  7. 7.
    Hoitsma E, et al. (2002) Small fibre neuropathy in sarcoidosis. Lancet. 359:2085–6.CrossRefGoogle Scholar
  8. 8.
    Uceyler N, et al. (2010) Elevated proinflammatory cytokine expression in affected skin in small fiber neuropathy. Neurology. 74:1806–13.CrossRefGoogle Scholar
  9. 9.
    Brines M, et al. (2004) Erythropoietin mediates tissue protection through an erythropoietin and common beta-subunit heteroreceptor. Proc. Natl. Acad. Sci. U. S. A. 101:14907–12.CrossRefGoogle Scholar
  10. 10.
    Bianchi R, et al. (2004) Erythropoietin both protects from and reverses experimental diabetic neuropathy. Proc. Natl. Acad. Sci. U. S. A. 101:823–8.CrossRefGoogle Scholar
  11. 11.
    Niesters M, et al. (2013) The erythropoietin-analogue ARA 290 for treatment of sarcoidosis-induced chronic neuropathic pain. Exp. Opin. Orphan Drugs. 1:77–87.CrossRefGoogle Scholar
  12. 12.
    Swartjes M, et al. (2011) ARA290, a peptide derived from the tertiary structure of erythropoietin, produces long-term relief of neuropathic pain: an experimental study in rats and beta-common receptor knockout mice. Anesthesiology. 115:1084–92.CrossRefGoogle Scholar
  13. 13.
    Costabel U, Hunninghake GW. (1999) ATS/ERS/WASOG statement on sarcoidosis. Sarcoidosis Statement Committee. American Thoracic Society. European Respiratory Society. World Association for Sarcoidosis and Other Granulomatous Disorders. Eur. Respir. J. 14:735–7.CrossRefGoogle Scholar
  14. 14.
    Rolke R, et al. (2006) Quantitative sensory testing: a comprehensive protocol for clinical trials. Eur. J. Pain 10:77–88.CrossRefGoogle Scholar
  15. 15.
    Magerl W, et al. (2010) Reference data for quantitative sensory testing (QST): refined stratification for age and a novel method for statistical comparison of group data. Pain. 151:598–605.CrossRefGoogle Scholar
  16. 16.
    De Vries J, Michielsen H, Van Heck GL, Drent M. (2004) Measuring fatigue in sarcoidosis: the Fatigue Assessment Scale (FAS). Br. J. Health Psychol. 9:279–91.CrossRefGoogle Scholar
  17. 17.
    Farrar JT, Dworkin RH, Max MB. (2006) Use of the cumulative proportion of responders analysis graph to present pain data over a range of cut-off points: making clinical trial data more understandable. J. Pain Symptom Manage. 31:369–77.CrossRefGoogle Scholar
  18. 18.
    Erckens RJ, Mostard RL, Wijnen PA, Schouten JS, Drent M. (2012) Adalimumab successful in sarcoidosis patients with refractory chronic non-infectious uveitis. Graefes. Arch. Clin. Exp. Ophthalmol. 250:713–20.CrossRefGoogle Scholar
  19. 19.
    Loza MJ, et al. (2011) Inflammatory profile and response to anti-tumor necrosis factor therapy in patients with chronic pulmonary sarcoidosis. Clin. Vaccine Immunol. 18:931–9.CrossRefGoogle Scholar
  20. 20.
    Hoitsma E, et al. (2006) Improvement of small fiber neuropathy in a sarcoidosis patient after treatment with infliximab. Sarcoidosis Vasc. Diffuse Lung Dis. 23:73–7.PubMedGoogle Scholar
  21. 21.
    Elfferich MD, et al. (2010) Everyday cognitive failure in sarcoidosis: the prevalence and the effect of anti-TNF-alpha treatment. Respiration. 80:212–9.CrossRefGoogle Scholar
  22. 22.
    Parambil JG, Tavee JO, Zhou L, Pearson KS, Culver DA. (2011) Efficacy of intravenous immunoglobulin for small fiber neuropathy associated with sarcoidosis. Respir. Med. 105:101–5.CrossRefGoogle Scholar
  23. 23.
    Wakasugi D, et al. (2009) Extreme efficacy of intravenous immunoglobulin therapy for severe burning pain in a patient with small fiber neuropathy associated with primary Sjogren’s syndrome. Mod. Rheumatol. 19:437–40.CrossRefGoogle Scholar
  24. 24.
    Tavee J, Zhou L. (2009) Small fiber neuropathy: a burning problem. Cleve. Clin. J. Med. 76:297–305.CrossRefGoogle Scholar
  25. 25.
    Brines M, Cerami A. (2008) Erythropoietin-mediated tissue protection: reducing collateral damage from the primary injury response. J. Intern. Med. 264:405–32.CrossRefGoogle Scholar
  26. 26.
    Brines M, Cerami A. (2012) The receptor that tames the innate immune response. Mol. Med. 18:486–96.CrossRefGoogle Scholar
  27. 27.
    Schmidt RE, et al. (2011) Effect of insulin and an erythropoietin-derived peptide (ARA290) on established neuritic dystrophy and neuronopathy in Akita (Ins2 Akita) diabetic mouse sympathetic ganglia. Exp. Neurol. 232:126–35.CrossRefGoogle Scholar
  28. 28.
    Gibbons CH, Wang N, Freeman R. (2010) Capsaicin induces degeneration of cutaneous autonomic nerve fibers. Ann. Neurol. 68:888–98.CrossRefGoogle Scholar

Copyright information

© The Author(s) 2012

Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, and provide a link to the Creative Commons license. You do not have permission under this license to share adapted material derived from this article or parts of it.

The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.

To view a copy of this license, visit (

Authors and Affiliations

  • Lara Heij
    • 1
  • Marieke Niesters
    • 1
  • Maarten Swartjes
    • 1
  • Elske Hoitsma
    • 2
  • Marjolein Drent
    • 3
    • 8
  • Ann Dunne
    • 4
  • Jan C. Grutters
    • 5
    • 6
  • Oscar Vogels
    • 7
  • Michael Brines
    • 4
  • Anthony Cerami
    • 1
    • 4
  • Albert Dahan
    • 1
  1. 1.Department of AnesthesiologyLeiden University Medical CenterLeidenThe Netherlands
  2. 2.Department of NeurologyDiaconessenhuisLeidenThe Netherlands
  3. 3.Faculty of Health, Medicine and Life ScienceUniversity of MaastrichtMaastrichtThe Netherlands
  4. 4.Araim PharmaceuticalsOssiningUSA
  5. 5.Department of PulmonologySt. Antonius Hospital NieuwegeinNieuwegeinThe Netherlands
  6. 6.Division of Heart and LungsUniversity Medical Center UtrechtUtrechtThe Netherlands
  7. 7.Department of NeurologySt. Antonius HospitalNieuwegeinThe Netherlands
  8. 8.Department of Interstitial Lung DiseasesHospital Gelderse ValleiEdeThe Netherlands

Personalised recommendations