New Use for LDN: Sarcoidosis Leonard Weinstock, MD Associate Professor of Clinical Medicine Washington University School of Medicine President, Specialists in Gastroenterology

Experiences with LDN “Conditions where LDN could be of benefit” “Conditions where LDN could be of benefit” 176 diseases, syndromes, and disorders 176 diseases, syndromes, and disorders Limited number of publications Limited number of publications

My LDN Experience: (N>1200) Alopecia areata Alopecia areata Chronic fatigue synd. Chronic fatigue synd. Complex regional pain * Complex regional pain * Constipation * Constipation * Crohn’s disease * Crohn’s disease * Dercum’s disease Dercum’s disease Eczema Eczema Fibromyalgia * Fibromyalgia * AIDS * AIDS * Interstitial cystitis Irritable bowel syndrome * Multiple sclerosis * Prostatitis (Type III) Restless legs syndrome Sarcoidosis Small intestinal bacterial overgrowth Ulcerative colitis *

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.

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.

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

Sarcoidosis: Standard Rx Initial therapy: prednisone (often 2 yr) with variable initial dose, taper, & duration Initial therapy: prednisone (often 2 yr) with variable initial dose, taper, & duration Steroid-sparing Rx: Steroid-sparing Rx: Methotrexate Methotrexate Azathioprine Azathioprine Leflunomide Leflunomide Mycophenolate Mycophenolate Infliximab Infliximab Baughman; Chapelon-Abric.

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

Sarcoidosis Rx: Role for LDN  Regulate T-cell growth   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

Sarcoid Case 1 RashFatigueAdenopathyLiver/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 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

11/ /2014 Before LDN

7/ mo LDN 12/ mo LDN

12/14 12/15 – 10 mo LDN

Sarcoid Case 2 PulmonaryFatigue

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

Case 2: PFB 64 y.o. AAF  9/15 – 1 mo LDN  No change  10/ 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 Pulmonary response w treadmill testing Pulmonary response w treadmill testing Anti-inflammatory markers Anti-inflammatory markers