Michael Brines

Corneal nerve quantification predicts the severity of symptoms in sarcoidosis patients with painful neuropathy

Small fiber neuropathy (SFN) is a debilitating condition characterized by chronic pain as well as sensory and autonomic dysfunction. SFN is an increasingly recognized component of a large number of diseases, including sarcoidosis. Although affecting an estimated 2–3% of the adult population in the United States, it often remains undiagnosed. Skin biopsy for evaluating intra-epidermal nerve fiber density (IENFD) and more recently corneal confocal microscopy (CCM) have been used to identify small fiber damage in patients with neuropathy. We demonstrate a significant reduction in IENFD, corneal nerve fiber number and length, with no change in the number of branches in patients with painful sarcoid neuropathy. Moreover, unlike IENFD, corneal nerve fiber number and length inversely correlate with the degree to which pain interferes with activities of daily living as assessed by the Brief Pain Inventory questionnaire. CCM thus constitutes an accurate, non-invasive assessment technique to aid in the diagnosis of SFN, as well as an objective marker of symptoms in patients with painful sarcoid neuropathy.

Targeting the innate repair receptor to treat neuropathy

Abstract The innate repair receptor (IRR) is a heteromer of the erythropoietin receptor and the &bgr;-common (CD131) receptor, which simultaneously activates anti-inflammatory and tissue repair pathways. Experimental data suggest that after peripheral nerve injury, the IRR is upregulated in the spinal cord and modulates the neurogenic inflammatory response. The recently introduced selective IRR agonist ARA290 is an 11-amino acid peptide initially tested in animal models of neuropathy. After sciatic nerve injury, ARA290 produced a rapid and long-term relief of mechanical and cold allodynia in normal mice, but not in animals with a &bgr;-common receptor knockout phenotype. In humans, ARA290 has been evaluated in patients with small fiber neuropathy associated with sarcoidosis or type 2 diabetes (T2D) mellitus. In patients with sarcoidosis, ARA290 significantly improved neuropathic and autonomic symptoms, as well as quality of life as assessed by the small fiber neuropathy screening list questionnaire. In addition, ARA290 treatment for 28 days initiated a regrowth of small nerve fibers in the cornea, but not in the epidermis. In patients with T2D, the results were similar to those observed in patients with sarcoidosis along with an improved metabolic profile. In both populations, ARA290 lacked significant adverse effects. These experimental and clinical studies show that ARA290 effectively reprograms a proinflammatory, tissue-damaging milieu into one of healing and tissue repair. Further clinical trials with long-term treatment and follow-up are needed to assess the full potential of IRR activation by ARA290 as a disease-modifying therapy in neuropathy of various etiologies.

Novel Applications for Recombinant Human Erythropoietin

Erythropoietin (EPO) is mainly produced in the kidney and plays a key role in the physiologic response to hypoxia by promoting increased red blood cell production. In addition, astrocytes and neurons in the central nervous system (CNS) produce EPO in response to hypoxia/ischemia. Data from preclinical studies have demonstrated the ability of recombinant human erythropoietin (r-HuEPO) to protect neurons from hypoxic/ischemic stress when administered intracerebroventricularly, suggesting that EPO may also have a neuroprotective role. In animal models of CNS disorders, systemically administered r-HuEPO has not been investigated in depth because it was assumed that large glycosylated molecules were not able to cross the blood-brain barrier (BBB). A collaborative research program identified the expression of EPO receptors on human brain capillaries and detected a specific receptor-mediated transport of r-HuEPO across the BBB after a single intraperitoneal (IP) injection in rodents, with subsequent protection against several kinds of neuronal damage. For example, administration of r-HuEPO 24 hours before or up to 6 hours after focal ischemic stroke significantly attenuated the magnitude of the infarction. r-HuEPO also reduced the extent of concussive brain injury, autoimmune encephalomyelitis, and kainate-induced seizures. These preclinical data suggest that r-HuEPO may have therapeutic potential in clinical settings such as in the treatment of stroke, head trauma, and epilepsy. Further studies are required to confirm and expand on these promising observations in animal models.