cibinetide and Sarcoidosis

Fatigue is a common manifestation of sarcoidosis, often persisting without evidence of disease activity. First-line therapies for sarcoidosis have limited effect on fatigue. This review aimed to assess the treatment options targeting sarcoidosis-associated fatigue. Medline and Web of Science were searched in November 2015; the bibliographies of these papers, and relevant review papers, were also searched. Studies were included if they reported on the efficacy of interventions (both pharmacological and non-pharmacological) on fatigue scores in sarcoidosis patients. Eight studies were identified that fulfilled the inclusion criteria. These studies evaluated six different interventions (infliximab, adalimumab, ARA 290, methylphenidate, armodafinil and exercise programmes). There is evidence to support a treatment effect of anti-tumour necrosis factor (TNF)-αtherapies (adalimumab and infliximab) and neurostimulants (methylphenidate and armodafinil), but within five of the studies, the risk of bias was high within most domains and the remaining three studies included only small numbers of participants and were short in duration. Trial evidence for treating fatigue as a manifestation of sarcoidosis is limited and requires further investigation. Anti-TNF-α therapies may be beneficial in patients with organ-threatening disease. Neurostimulants have some trial evidence supporting improvements in fatigue but further investigation is needed before they can be recommended.

Topics: Adalimumab; Antirheumatic Agents; Benzhydryl Compounds; Central Nervous System Stimulants; Exercise Therapy; Fatigue; Humans; Infliximab; Methylphenidate; Modafinil; Oligopeptides; Sarcoidosis; Tumor Necrosis Factor-alpha

Painful peripheral neuropathy is a common, difficult-to-treat complication associated with a variety of diseases, including diabetes mellitus and sarcoidosis. It is caused by damage of small and autonomic nerve fibers, resulting in potentially debilitating symptoms of neuropathic pain and autonomic dysfunction. The limited efficacy of current treatment options dictates a rationalized design of novel compounds.. The authors present the recent data from two Phase II clinical trials on ARA290, an erythropoietin derivative with tissue protective and healing properties that does not stimulate erythropoiesis. ARA 290 treatment was consistently associated with a significant improvement of neuropathic pain symptoms in sarcoidosis patients, evidenced by a decrease in pain scores on validated questionnaires. Moreover, ARA 290 treatment resulted in significant increases in corneal nerve fibers, improved sensory pain thresholds, improved quality of life and physical functioning.. Current treatment modalities of neuropathy are based on a trial-and-error approach, have limited efficacy and come with significant side effects. Given the excellent safety profile while reducing neuropathy symptoms, the prospects of ARA 290 treatment in sarcoid neuropathy seem promising. The long-lasting beneficial effects of ARA 290 on both pain-related and non-pain-related symptoms in sarcoidosis patients prompt additional studies on potential disease-modifying properties of ARA 290.

Topics: Analgesics; Animals; Erythromelalgia; Humans; Neuralgia; Oligopeptides; Sarcoidosis; Treatment Outcome

Sarcoidosis frequently is complicated by small nerve fiber loss (SNFL), which can be quantified using corneal confocal microscopy (CCM). Prior studies suggest that the innate repair receptor agonist cibinetide reverses corneal nerve loss. This phase 2b, 28-day, randomized trial of 64 subjects with sarcoid-associated SNFL and neuropathic pain assessed the effect of cibinetide on corneal nerve fiber area (CNFA) and regenerating intraepidermal fibers (GAP-43+) as surrogate endpoints for disease modification, pain severity, and functional capacity (6-minute walk test [6MWT]).. Cibinetide (1, 4, or 8 mg/day) was compared to placebo. The primary study endpoint was a change in CNFA at 28 days.. The placebo-corrected mean change from baseline CNFA (μm2) at day 28 was 109 (95% confidence interval [CI], -429, 647), 697 (159, 1236; P = 0.012), and 431 (-130, 992) in the 1, 4, and 8 mg groups, respectively. Intraepidermal GAP-43+ fibers increased in the 4 mg group (P = 0.035). Further, changes in CNFA correlated with changes in GAP-43+ (ρ = 0.575; P = 0.025) and 6MWT (ρ = 0.645; P = 0.009). Pain improved significantly in all groups, with subjects having moderate-severe pain reporting a clinically meaningful placebo-corrected decrease in pain intensity in the 4 mg group (P = 0.157).. Cibinetide significantly increased small nerve fiber abundance in the cornea and skin, consistent with a disease modifying effect. The relationships between CNFA and other clinical measures of disease support its use as a surrogate endpoint to assess potential disease modifying therapies for neuropathy.

Topics: Adolescent; Adult; Aged; Cornea; Dose-Response Relationship, Drug; Double-Blind Method; Female; Follow-Up Studies; Humans; Male; Microscopy, Confocal; Middle Aged; Nerve Fibers; Neuralgia; Oligopeptides; Retrospective Studies; Sarcoidosis; Treatment Outcome; Young Adult

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.

Topics: Cornea; Drug Administration Schedule; Erythromelalgia; Exercise Test; Female; Humans; Injections, Subcutaneous; Male; Microscopy, Confocal; Middle Aged; Nerve Fibers; Oligopeptides; Sarcoidosis

Topics: Cornea; Erythromelalgia; Female; Humans; Male; Oligopeptides; Sarcoidosis