LDN for Autoimmune and Inflammatory Diseases Leonard Weinstock

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

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

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

LDN Hx: Modulator of Opioid & Receptor Activity (MORA) n 1979 -81: MOA studied (Zagon – Penn State) n 1985: Rx for AIDS (Bihari) n Mid 90’s: Rx for MS (Bihari) n LDN = low dose naltrexone (1. 0 - 4. 5 mg/d) vs. 50 mg– 100 mg daily for opiate and alcohol dependence (FDA IND 1985) vs. Zagon et al. Science 1983; 221: 671 -3.

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

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

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

Methionine enkephalin: role in immunoregulation n MENK binds to opioid receptors on immune and cancer cells. Binding site: CD 4+Foxp 3+ 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.

MENK & immunology & cancer n n n MENK delayed development of tumor in S 180 tumor bearing mice and downregulated level of Tregs Cancer study – 50 pts – isolated lymphocyte subpopulation evaluations in peripheral blood before and after culture with MENK inhibited CD 4+T cells, CD 8+T cells, CD 4+CD 25+ Tregs and natural killer cells Wang. Hum Vaccin Immunother 2014; 10: 1836 -40.

LDN MOA n 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. n Endorphins now interact with the more-sensitive and more-plentiful receptors and assist in regulating cell

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

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

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

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

Case 1 n Addition of LDN 4. 5 mg n Endoscopic and sx’ic remission within 2 mo

Crohn’s disease – 3 open label studies • 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.

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

Crohn’s disease – RCT #1 • LDN as adjunctive therapy in adults • Biologic therapy was an exclusion • 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 • 33% of LDN had endoscopic remission vs. 8% controls Smith et al. Dig Dis Sci 2011; 56: 2088 -97.

Crohn’s disease – RCT #2 • LDN as sole therapy in 14 children • LDN (0. 1 mg/kg) vs. placebo for 8 wks • CDAI: 34± 3 decreased to 22± 4 CDAI: (P=0. 005) • 25% went into remission • No serious AE Smith et al. J Clin Gastroenterol 2013; 47: 339 -345.

Fibromyalgia: RTC study • LDN 4. 5 mg/day vs. placebo • N=31 women • Randomized, double-blind, placebocontrolled, counterbalanced, x-over study. • Questionnaires to measure daily levels of pain. Secondary outcomes included general satisfaction with life, positive mood, sleep quality and fatigue Younger et al. Arthritis Rheum 2013 Feb; 65: 52938.

Fibromyalgia: RTC study • LDN 4. 5 mg/day vs. placebo • N=31 women • Randomized, double-blind, placebocontrolled, counterbalanced, x-over study. • Questionnaires to measure daily levels of pain. Secondary outcomes included general satisfaction with life, positive mood, sleep quality and fatigue Younger et al. Arthritis Rheum 2013 Feb; 65: 52938.

Fibromyalgia: RTC study (cont. ) • 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) • 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 Younger et al. Arthritis Rheum 2013 Feb; 65: 529 -

Sarcoidosis Granulomatous disorder with T-cells & macrophages in multiple organs § CD 3+ cells, CD 4+ cells w/ HLA-DR antigen, & high CD 4/CD 8 ratio in bronchus § CD 4+ CD 29+ memory T-cells increased Iida K et al. Thorax 1997; 52: 431 -7.

Sarcoidosis § Special T-cell interactions in pulmonary and liver sarcoidosis § Activated memory T-cells with CD 11 a Iida K et al. Thorax 1997; 52: 431 -7.

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

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

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 TH 2 to TH 1 Improve GI motility

Sarcoid Case 1 Rash Fatigue Adenopathy Liver/Spleen

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

Progress 2015 February - LDN 1 mg/day n March - less dyspnea, fatigue, able to stop minocycline w/o rash n March – LDN increased 12 days to 4. 5 mg n May – Dec - less DOE, more energy n July & Dec – CT’s showed reduction in the size of the splenic lesions and n

12/2014 11/2011 Before LDN

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

12/15 – 10 mo LDN 12/14

Sarcoid Case 2 Pulmonary Fatigue

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

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

Sarcoid Case 3 Pulmonary

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)

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

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

LDN side effects: neurologic n Anxiety 15. 7% n Drowsiness 11. 6% n Headache 11. 6% n Insomnia 8. 3% n Muscle pain 8. 3% n Vivid dreams 5. 0% n Mood change 3. 3% n Trouble concentration 1. 7% Ploesser J, Weinstock LB, Thomas E. Internat J Pharm Compound 2010: 171 -173.

LDN: additional side effects n Nausea 12. 4% n Abd. pain 11. 6% n Diarrhea 8. 3% n Anorexia 8. 3% n 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.