1. LDN for Autoimmune and Inflammatory Diseases Leonard Weinstock, MD Associate Professor of Clinical Medicine Washington University School of Medicine President, Specialists in Gastroenterology

2. LDN Rx at SIG: 2005-2016, N>1400 Alopecia areata Alopecia areata Chronic fatigue synd. Chronic fatigue synd. Chronic pelvic pain Chronic pelvic pain Complex regional pain ^ Complex regional pain ^ Constipation * Constipation * Dercum’s disease Dercum’s disease Eczema Eczema Fibromyalgia * Fibromyalgia * Ganglionopathy ^ HIV * Inflammatory bowel dis. *^ Inflammatory bowel dis. *^ Irritable bowel syndrome * Multiple sclerosis *^ Restless legs syndrome * Rheumatoid arthritis Sarcoidosis ^ SIBO * * Published; ^ To be discussed

3. Outline History of LDN History of LDN Mechanisms of action of LDN Mechanisms of action of LDN Autoimmune and inflammatory diseases Autoimmune and inflammatory diseases Crohn’s disease Crohn’s disease Ulcerative colitis Ulcerative colitis Sarcoidosis Sarcoidosis Autonomic ganglionopathy Autonomic ganglionopathy Complex regional pain syndrome Complex regional pain syndrome Multiple sclerosis Multiple sclerosis

4. LDN Hx: Modulator of Opioid & Receptor Activity (MORA) 1979-81: MOA studied (Zagon – Penn State) 1979-81: MOA studied (Zagon – Penn State) 1985: Rx for AIDS (Bihari) 1985: Rx for AIDS (Bihari) Mid 90’s: Rx for MS (Bihari) Mid 90’s: Rx for MS (Bihari) LDN = low dose naltrexone (1.0- 4.5 mg/d) LDN = low dose naltrexone (1.0- 4.5 mg/d) vs. 50mg–100mg daily for opiate and alcohol dependence (FDA IND 1985) vs. ultra low dose 0.001 mg in Oxytrex Zagon et al. Science 1983;221:671-3.

5. Endogenous opioids & receptors Peptides: B-endorphin, enkephalins, endomorphin, dynorphin Peptides: B-endorphin, enkephalins, endomorphin, dynorphin Receptors Receptors CNS and PNS CNS and PNS GI tract GI tract Myenteric plexus Myenteric plexus Mucosal plexus Mucosal plexus Endocrine cells of intestinal mucosa Endocrine cells of intestinal mucosa Lymphocytes Lymphocytes

6. Endorphins Endorphins produced in most cells Endorphins produced in most cells Regulate cell growth including immune cells Regulate cell growth including immune cells Disorders of the immune system can occur with unusually low levels of these endorphins Disorders of the immune system can occur with unusually low levels of these endorphins Met-Enkephalin is the most influential endorphin Met-Enkephalin is the most influential endorphin

7. Opioid Growth Factor (OGF) Met-Enkephalin = Opioid Growth Factor Met-Enkephalin = Opioid Growth Factor OGF binds to the Opioid Growth Factor Receptor (OGFr) OGF binds to the Opioid Growth Factor Receptor (OGFr) Two elements are required for health: opioid production and cell interaction Two elements are required for health: opioid production and cell interaction

8. Methionine enkephalin: role in immunoregulation MENK binds to opioid receptors on immune and cancer cells. Binding site: CD4+Foxp3+ regulatory T cells (Tregs) which suppressing immune system to keep balanced immunity Tregs reveal a relationship between the endocrine and immune systems Zhao. Int Immunopharmacol 2016;37:59-64. Li. Cancer Biol Ther 2015;16:450-9.Cancer Biol Ther

9. MENK & immunology & cancer MENK delayed development of tumor in S180 tumor bearing mice and down-regulated level of Tregs Cancer study – 50 pts – isolated lymphocyte subpopulation evaluations in peripheral blood before and after culture with MENK MENK inhibited CD4+T cells, CD8+T cells, CD4+CD25+ Tregs and natural killer cells WangWang. Hum Vaccin Immunother 2014;10:1836-40.Hum Vaccin Immunother

10. LDN MOA LDN blocks the OGF receptors only for a few hours – leads to a rebound effect; in which both the production and utilization of OGF is greatly increased. Endorphins now interact with the more- sensitive and more-plentiful receptors and assist in regulating cell growth and immunity

11. LDN MOA Reduces/regulated T-cells, Natural Killer cells, IL-2 and TH-1 improve native immune system Shift from TH1 to TH2 decreases general inflammation

12. Additional MOA – Toll receptors Endothelial receptors – possible MOA for IBD Endothelial receptors – possible MOA for IBD GI receptor allows for increase in bacterial translocation – exacerbated by exogenous opioids GI receptor allows for increase in bacterial translocation – exacerbated by exogenous opioids LDN may stabilize receptor and decrease bacterial translocation LDN may stabilize receptor and decrease bacterial translocation Glial receptor Glial receptor Activated microglia cause neuroexitability and enhanced pain via toll-like receptor 4 pathway Activated microglia cause neuroexitability and enhanced pain via toll-like receptor 4 pathway LDN antagonizes pathway LDN antagonizes pathway Li. Med Hypotheses 2012;79:754-6. Hutchinson et al. Brain Behav Immun 2010;24:83-95.

13. LDN & inflammatory bowel diseases First reported in Crohn’s disease Subsequently reported in ulcerative colitis Both related to autoimmune, inflammatory, and microbiome disturbances with active cytokines

14. Case 1 40 y.o. WF with Crohn’s disease – s/p total colectomy, recurrence in ileum 4 yrs later 40 y.o. WF with Crohn’s disease – s/p total colectomy, recurrence in ileum 4 yrs later Failing infliximab: diarrhea and fatigue Failing infliximab: diarrhea and fatigue

15. Case 1 Addition of LDN 4.5 mg Addition of LDN 4.5 mg Endoscopic and sx’ic remission within 2 mo Endoscopic and sx’ic remission within 2 mo

16. Crohn’s disease – 3 open label studies Smith. LDN therapy improves active Crohn's disease. Am J Gastroenterol 2007;102:820-828. Smith. LDN therapy improves active Crohn's disease. Am J Gastroenterol 2007;102:820-828. Shannon. LDN for treatment of duodenal Crohn’s disease in a pediatric patient. Inflamm Bowel Dis 2010;16:1457. Shannon. LDN for treatment of duodenal Crohn’s disease in a pediatric patient. Inflamm Bowel Dis 2010;16:1457.

17. Crohn’s disease - LW Open label study: 4.5 mg LDN in moderate to severe CD (N=33 adults) Failing 5-ASA followed by 6-MP and/or IFX LDN Rx: 40 ±43 wks (max 200 wks) 5 withdrew - AE (mild-mod) Positive clinical response in 15/33 pts 11 of 15 responders: C-scope before and after Rx: 8 complete healing, 1 partial healing and 2 unchanged Weinstock. J Clin Gastro 2014

18. Crohn’s disease – RCT #1 Smith et al. Dig Dis Sci 2011;56:2088-97. LDN as adjunctive therapy in adults LDN as adjunctive therapy in adults Biologic therapy was an exclusion Biologic therapy was an exclusion 88% of LDN (N=18) had 70-point decrease in CDAI scores vs. 40% of control (N=16) 88% of LDN (N=18) had 70-point decrease in CDAI scores vs. 40% of control (N=16) After 12 wks, 78% of LDN had response in CD endoscopy index severity score vs. 28% controls After 12 wks, 78% of LDN had response in CD endoscopy index severity score vs. 28% controls 33% of LDN had endoscopic remission vs. 8% controls 33% of LDN had endoscopic remission vs. 8% controls

19. Crohn’s disease – RCT #2 J Clin Gastroenterol 2013;47:339-345. Smith et al. J Clin Gastroenterol 2013;47:339-345. LDN as sole therapy in 14 children LDN as sole therapy in 14 children LDN (0.1 mg/kg) vs. placebo for 8 wks CDAI: CDAI: 34±3 decreased to 22±4 (P=0.005) 25% went into remission No serious AE No serious AE

20. Fibromyalgia: RTC study Younger et al. Arthritis Rheum 2013 Feb;65:529-38. LDN 4.5 mg/day vs. placebo LDN 4.5 mg/day vs. placebo N=31 women N=31 women Randomized, double-blind, placebo- controlled, counterbalanced, x-over study. Randomized, double-blind, placebo- controlled, counterbalanced, x-over study. Questionnaires to measure daily levels of pain. Secondary outcomes included general satisfaction with life, positive mood, sleep quality and fatigue Questionnaires to measure daily levels of pain. Secondary outcomes included general satisfaction with life, positive mood, sleep quality and fatigue

21. Fibromyalgia: RTC study Younger et al. Arthritis Rheum 2013 Feb;65:529-38. LDN 4.5 mg/day vs. placebo LDN 4.5 mg/day vs. placebo N=31 women N=31 women Randomized, double-blind, placebo- controlled, counterbalanced, x-over study. Randomized, double-blind, placebo- controlled, counterbalanced, x-over study. Questionnaires to measure daily levels of pain. Secondary outcomes included general satisfaction with life, positive mood, sleep quality and fatigue Questionnaires to measure daily levels of pain. Secondary outcomes included general satisfaction with life, positive mood, sleep quality and fatigue

22. Fibromyalgia: RTC study (cont.) Younger et al. Arthritis Rheum 2013 Feb;65:529-38. 28.8% pain reduction with LDN vs. 18.0% reduction with placebo (P = 0.016) 28.8% pain reduction with LDN vs. 18.0% reduction with placebo (P = 0.016) LDN improved general satisfaction with life (P = 0.045) and improved mood (P = 0.039) LDN improved general satisfaction with life (P = 0.045) and improved mood (P = 0.039) 32% had a significant reduction in pain plus a significant reduction in either fatigue or sleep problems vs. 11% response rate with placebo (P = 0.05) 32% had a significant reduction in pain plus a significant reduction in either fatigue or sleep problems vs. 11% response rate with placebo (P = 0.05) LDN equally tolerable as placebo. No serious side effects were reported LDN equally tolerable as placebo. No serious side effects were reported

23. Sarcoidosis Granulomatous disorder with T-cells Granulomatous disorder with T-cells & macrophages in multiple organs & macrophages in multiple organs  CD3+ cells, CD4+ cells w/ HLA-DR antigen, & high CD4/CD8 ratio in bronchus  CD4+ CD29+ memory T-cells increased Iida K et al. Thorax 1997;52:431-7.

24. Sarcoidosis  Special T-cell interactions in pulmonary and liver sarcoidosis  Activated memory T-cells with CD11a Iida K et al. Thorax 1997;52:431-7.

25. Sarcoidosis: Pathogenesis Genetic susceptibility with functional polymorphisms Genetic susceptibility with functional polymorphisms Exposure to antigens leading to activation of macrophages Exposure to antigens leading to activation of macrophages Attainment of T-cell immunity against antigens mediated by antigen processing and presentation by macrophage Attainment of T-cell immunity against antigens mediated by antigen processing and presentation by macrophage Zissel

26. Sarcoidosis vs. Crohn’s disease  Similar pathology  Unregulated T-cell activity  Non-caseating granulomas

27. Sarcoidosis Rx: Role for LDN  Regulate T-cell growth – (Treg)   Regulate B-cell growth   Decrease inflammation   Decrease permeability   Stabilize Toll-like receptors   Decrease microglia activation   Decrease cytokine release   Shift from TH2 to TH1   Improve GI motility

28. Sarcoid Case 1 RashFatigueAdenopathyLiver/Spleen

29. Case 1 AH 73 y.o. AAF – supraglotic resection in 2001 d/t sarcoidosis. Sx weak voice, painful rash, fatigue, and parotitis  Rash prevention by minocycline  Hx MTX neuropathy  Referred abnl CT  LDN – prescribed

30. Progress 2015 February - LDN 1 mg/day March - less dyspnea, fatigue, able to stop minocycline w/o rash March – LDN increased 12 days to 4.5 mg May – Dec - less DOE, more energy July & Dec – CT’s showed reduction in the size of the splenic lesions and liver lesions

31. 11/2011 12/2014 Before LDN

32. 7/15 - 5 mo LDN 12/12 - 10 mo LDN

33. 12/14 12/15 – 10 mo LDN

34. Sarcoid Case 2 PulmonaryFatigue

35. Case 2: PFB 64 y.o. AAF  26 yr pulmonary sarcoidosis  2 yr home O2 (24 hr/d; 2 L)  Dyspnea (rest/activity) and dry cough  7/15 - Prednisone 20 mg  Last used 16 yr ago  8/15 - LDN

36. Case 2: PFB 64 y.o. AAF  9/15 – 1 mo LDN  No change  10/15 - 2 mo LDN  Less fatigue  Less dyspnea  O 2 prn for vigorous activity  Prednisone taper started

37. Sarcoid Case 3 Pulmonary

38. Case 3: PLB 63 y.o. WM  Abnl CXR 17 yr ago – Bx: granulomas  Hx osteopenia  2 yrs dyspnea with activity  8/20/15 - LDN  4.5 mg (titrated up from 1.5 over 2 wks)

39. Case 3: PLB 63 y.o. WM  1 mo after LDN – unchanged  2 mo after LDN – less short of breath  3 mo after LDN – asthma from allergens

40. Sarcoidosis Rx: Role for LDN Experience needed – enroll AA pts Pulmonary response w treadmill testing Pulmonary response w treadmill testing Anti-inflammatory markers Anti-inflammatory markers

41. LDN side effects: neurologic Anxiety 15.7% Anxiety 15.7% Drowsiness 11.6% Drowsiness 11.6% Headache 11.6% Headache 11.6% Insomnia 8.3% Insomnia 8.3% Muscle pain 8.3% Muscle pain 8.3% Vivid dreams 5.0% Vivid dreams 5.0% Mood change 3.3% Mood change 3.3% Trouble concentration 1.7% Trouble concentration 1.7% Ploesser J, Weinstock LB, Thomas E. Internat J Pharm Compound 2010:171-173.

42. LDN: additional side effects Nausea 12.4% Nausea 12.4% Abd. pain 11.6% Abd. pain 11.6% Diarrhea 8.3% Diarrhea 8.3% Anorexia 8.3% Anorexia 8.3% Rash, hot flashes, weight gain 0.1% each Rash, hot flashes, weight gain 0.1% each Ploesser J, Weinstock LB, Thomas E. Low Dose Naltrexone: Side Effects and Efficacy in Gastrointestinal Disorders. Internat J Pharm Compound 2010:171-173.