1. Neuroinflammatory Reflex
Implications on rheumatic disease
Immunology
Neuroscience

2. #1 Neutrophil and monocyte recruitment to the site of infection/injury

3. #2 Pathogen fragments and molecules involves with tissue injury stimulate TLR and other pattern recognition receptors

4. #3 Immune activation through NF-kappa-B

5. #4 Recruitment of adaptive immune cells

6. #5 Resolution of inflammation via resolving and lipoxins

7. Principles
Bi-direction communication between the periphery and the CNS
Reflex like circuits exist to quickly respond to inflammatory events

8. Vagal Physiology
Afferent fibers transmit information from peripheral organs to the brain

9. Vagal Physiology
Efferent fibers originate in the brain stem and innervate organs to control heart rate, GI motility and immune function

10. Vagal Physiology
Efferent vagus nerve communicates with the splenic nerve to suppress excessive pro- inflammatory cytokine responses and inflammation

11. Vagal Physiology
Acetyl- choline suppresses endotoxin- stimulated macrophage release of TNF, IL-1b, IL-6 and IL-18

12. Vagal Physiology
Afferents can stimulate the HPA axis and lead to release of cortisol by the adrenal gland

14. Pavlov Immunol Res (2015) 63:38–57

15. Vagus Nerve Interventions
Vagus Nerve Stimulator
18 pts for 84 days
stimulated up to 4x daily
57% achieved ACR50
30% resistant pts ACR50
28% DAS-28 remission
Frieda A. Koopman, et al. Vagus nerve stimulation inhibits cytokine production and attenuates disease severity in rheumatoid arthritis. PNAS, July 2016

16. Biologics
Generally ~50% of the patients have clinically relevant improvement (ACR20)1
1. Rheumatology (Oxford) Aug 14

17. Vagus Nerve Interventions
Transcutaneous TENS device
Improves heart rate variability 20% in 15minutes
Has not been studied in rheumatologic disease
Inexpensive and safe
Jennifer A. Clancy, et al. Non-invasive Vagus Nerve Stimulation in Healthy Humans Reduces Sympathetic Nerve Activity. Brain Stimulation, 2014; DOI: /j.brs

18. Vagus Nerve Interventions
Mid tech:
Cryo helmets
PEMF stimulators
Low Tech:
Deep breathing
Facial ice bathes
Cold showers
Gargling
Valsalva
Laughing
Singing
Gagging

19. Endogenous Opioids and Immune Function

20. Low Dose Naltrexone
Monocytes isolated from RA/SLE patients have low levels of beta endorphin
Lower levels of beta endorphin are inversely correlated with inflammatory markers
Levels are 1/4 -1/8 of a normal healthy population
WHY?
Wiedermann CJ, Sacerdote P, Mur E, Kinigadner U, Wicker T, Panerai AE, et al.Decreased immunoreactive beta-endorphin in mononuclear leucocytes frompatients with rheumatic diseases. Clin Exp Immunol 1992;87:178–82.
Panerai AE, Vecchiet J, Panzeri P, Meroni P, Scarone S, Pizzigallo E, et al. Peripheral blood mononuclear cell beta-endorphin concentration is decreased in chronic fatigue syndrome and fibromyalgia but not in depression, preliminary report. Clin J Pain 2002;18:270–3

21. Low Dose Naltrexone “The bio equivalent of an orgasm a day”- me
Modulated opioid growth factor (OGF) production and OGF receptors
Immunomodulating rather then suppressive

23. LDN Increasing beta endorphins and OGF sensitivity decreases:
IL1, TNFa production
TLR4 activity
Auto reactive T cell proliferation
Glial activation
Mitochondrial apoptosis

24. LDN Principles of prescribing
1.5mg caps PO HS x 7 nights, then 2 PO HS (3.0mg) x 7 nights, then 3 PO HS (4.5), then best tolerated dose thereafter
Use up to 6mg total dose depending on body weight
In pediatric patients >18months: 0.1mg/kg dosage
Avoid in pregnancy/early lactation
Avoid concurrent narcotic prescriptions**
**maybe