Rosacea and GI disorders Inflammation and Dysbiosis Leonard Weinstock, MD Associate Professor of...

Rosacea and GI disordersInflammation and Dysbiosis

Leonard Weinstock, MD

Associate Professor of Clinical MedicineWashington University in St. Louis

Specialists in Gastroenterology

Disclosures Speaker’s Bureau:

Salix (Relistor), Ironwood (Linzess)

Research grants:

Salix (Xifaxan - rifaximin)

Consultant:

Salix (Relistor)

Off label use of medicine:

In context of published research and FDA IND applications for new research

49 y.o. man • 3 yr Hx rosacea:

• E/F/Pap• Failed 2 topical Abx

• Started 4 months after food poisoning

• Mild bloating

• Dx: bacterial overgrowth

“Post-infectious Rosacea”

“Rosacea-SIBO”

42 F s/p Mont. revenge 13 yrs ago followed by:

– E/F/Phymaand ocular rosacea– Nail disorder

– IBS-c– Cognitive dysfx– Fatigue– RLS

– Steatohepatitis– Type 2 DM

Dx: Bacterial overgrowth

0 30 45 60 75 900

5

10

15

20

25

30

35

40

45

H2

CH4

Review

• Gut microbiome

• History of rosacea & gut

• Small intestinal bacterial overgrowth

• Enteric infections lead to diseases

• Antibiotic Rx for Rosacea-SIBO

• Additional SIBO diseases and rosacea

• Theories for shared pathophysiology

Gut vs. skin

• 100 SF

• Barrier with vascular & nerve interface

• Bacteria (100 trillion)

• > 500 types

• Commensal when in balance and with normal innate and systemic immunity

• 10 SF

• Barrier with vascular & nerve interface

• Bacteria (and mites)

• > 200 types

• Non-invasive when in balance and with normal innate and systemic immunity

Gut + microbiome > skin + spleen

Largest immune system

Normal host prevents dysbiosis

Stomach0 - 1000 oral bacteria (streptococcus, lactobacillus)

Colon100,000,000,000,000coliforms

(bacteroides, firmicutes, bifidobacter, clostridium)

Distal ileum100,000,000 -1,000,000,000coliforms

Duodenum & Jejunum 1,000 oral bacteria

Proximal ileum 10,000 oral bacteria

Acid

Motility

ICV

Pancreas

Mucosalabsorption

Immunity

Colon bacterial balance, integrity & immunity

Mondot. Dig Dis 2013;31:278-85.

Effects of dysbiosis

• Abnormal anatomy – Leaky tight-junctions

--- incr. intestinal permeability– Thinner lamina propria, shallow crypts– Abnormal Peyer’s patches, fewer plasma cells

• Immune disorders:– Altered cytokine profile

– Altered innate immune response (Th2 to Th1, IL-17)

– Diseases: atopy, diabetes, obesity, autoimmune

Bateman. Color Atlas of Dermatology. 1817. Text: “Rosacea and acne. Constipation.”

History of rosacea and the gut

• Alcohol & obesity – 13th century (Chaucer) (? Steatohepatitis)

• Dyspepsia – 1895• Food intolerance/allergies – 1926-1966• Achlorhydria – 1935, 1941• Gastritis – 1941• Celiac/jejunal diseases – 1965, 1970• Chronic pancreatitis – 1982• H. pylori – 1990’s• IBD: UC 1989; CD 2000 (drug-induced, PPR, R. fulminans,

granulomatous R.)

• Small intestinal bacterial overgrowth: 2008

Early text and rosacea- associated disorders

Kaposi. Pathology and Treatment of Disease of the Skin. 1895.

Textbooks and rosacea- associated disorders

• GI disorders (dyspepsia, diarrhea, constip) 1

• H. pylori: Coincidental 2, 3, plausible 4, undecided 5

• Parkinson’s disease 1, 2

• Hormonal changes 3

• Menopause 2 • Migraine 1-3

• Orthostatic hypotension 1

• Vasoactive tumors 2 • HIV 4, 5

• CNS tumors 1

1. Pelle. In Fitzpatrick 2012. 2. Webster. In Bolognia 2008. 3. In McKae 2005.4. Berth-Jones. In Rooks 2004. 5. Plewig, Klingman. In Acne

and Rosacea 2000.

Small intestinal bacterial overgrowth

and rosacea

First report in 2008

SIBO syndrome• Definition

– >105 colony forming units/mL in jejunum

– Sx and/or signs of malabsorption

• Treat 1o small bowel abnormality – “Often impractical”

• Antibiotics – Absorption and resistance concerns

• Motility drugs – Limited medications

• Intestinal permeability – Not addressed

Gregg CR, Toakes PP. In Sleisenger and Fortran. Gastrointestinal and Liver Disease.

Lactulose breath test

gas chromatography

• No gold standard to Dx SIBO - culture problems• Bacteria may be in various locations in the small bowel• Difficult to culture anaerobes

0

10

20

30

40

50

60

70

15 30 45 60 75 90 105 120 135 150 165 180

Time (in minutes)

Hyd

roge

n (p

pm)

Normal SIBO

Early rise in H2 (or CH4) in SIBO

Textbook SIBO

Scleroderma * Achlorhydria *

Small intestinal pseudo-obstruction Diabetes *

Pancreatic insufficiency * Radiation enteritis

Jejunal diverticulosis

Immunodeficiency: CLL, IgA def.,

T-cell def.

Post-surgical anatomy:

Billroth, Blind-loop ICV resect., J-pouch

SIBO – full blown

• Symptoms• Pain• Bloating• Diarrhea• Foul flatus• Weakness • Weight loss

• Signs and Labs• Edema• Anemia • Cachexia• Iron def.• Vitamin def.• Nutrient def.

“New” SIBO

• Crohn’s dis. *• Celiac dis. *• Irritable bowel synd. *• Chronic liver dis. *

• Restless legs synd. • Rosacea • Parkinson’s dis. *

* Associated with rosacea

• Renal failure• Hypothyroidism• Acromegaly• Post-chemotherapy• Fibromyalgia• Rheumatoid arthritis *• Interstitial cystitis• Chronic prostatitis

Weinstock. Dig Dis Sci 2010;55:1667-73.; Weinstock. Inflam Bowel Dis 2010;16:275-9.; Pimentel. N Engl J Med 2011;364:22-32. Walters, Weinstock. Sleep Med 2011;12:610-3.; Bellot . Liver Int 2013;33:31-9.; Parodi. Clin Gastroenterol Hepatol 2008;6:759-764.; Fasano. Mov Disord 2013;28:1241-9.; Weinstock. Dig Dis Sci 2008;53:1246-51.; Geng. Can J Urology 2011;18:5826-30.

Diseases after GI infections

Guillain-Barré syndrome

Celiac disease

Reactive arthritis

Pancreatitis

IBS – 20% recall infection first

Koga. J Infect Dis 2006;193:547-55.Yu. Rheum Dis Clin Noth Am 2003;29:21-36

Stene. Am J Gastroenterol 2006;101:2333-40.

Molecular mimicry & autoimmune pathwayswith genetic predisposition

Post-infectious IBS & associated syndromes

Infection in gut

Motility leads to SIBO

Pi-IBS, FMS, RLS,

CPPS

Genetic phenotype (low IL-10) for IBS

Pi-IBS

• 7 studies/2056 people: incidence 7-30%• Duration: 50-100% life-long (2 studies)• Pathophysiology:

– Weak MMC leads to SIBO

– Rat model: Camphylobacter caused SIBO in 27%

– Anti-vinculin antibody studies• Rats AVA led to loss of myenteric nerves• Patients with Pi-IBS have AVA

Pimentel 2004, 2011, 2013

Anti-vinculin Ab (AVA)

• Vinculin - involved in adhesion between cells– Skeletal muscle and nerves – Epineurial blood vessel smooth muscle – Endoneurium endothelial cells (EC)

• Theoretical role in vascular changes of rosacea and neurologic balance in neurogenic rosacea: AVA might damage EC & nerves especially in Pi-Rosacea

Pimentel. Abstract. ACG; Am J Gastroenterol; October 2013.Massa et al. Muscle Nerve 1995;18:1277–84.

Inflammation in SIBO & IBS

Riordin. Scand J Gastroenterol 1996;31:977-84.Lin. JAMA 2004;292:852-8.

Hughes et al. Am J Gastroenterol 2013;108:1066-74.Martinez et al. Gut 2013;62:1160-8.

• Interleukins – IL 1ß, 6, 8**, 12

• TNF-α (inflm. & incr. intestinal perm.)

• LPS (inflm. & incr. endothelial cell perm.)

• T- and B-lymphocytes – imbalance/activity

• Mast cells infiltration in gut

• Increased histamine, tryptase and seratonin

• Substance P (neuropeptide)

• Integrin Beta-7 T-lymphocytes (incr. vascular perm.)

• A-V Ab

Systemic cytokines in rosacea

Salamon. Przegi Lek 2008;65:371-4.

• 60 rosacea pts vs. 25 controls

• IL-18: 163 vs. 16 pg/ml (P<0.01)

• IL-6 lower in rosacea • TNF-alpha numerically higher • IL-8 not measured

Changing roles of antibiotic Rx

• 1950’s: Tetracycline

• 2000: low dose doxycycline• Inhibition of matrix metalloproteinases• Inflammatory cytokine regulation• Inhibition of leukocyte chemotaxis & activation and anti-oxidation• Antibiotic effect on stratum corneum tryptic enzymes (SCTEs)

• 2008: rifaximin for rosacea-SIBO

Parodi et al. Am J Gastroenterol 2008;6:759-764.

Rifaximin – semi-sythetic

RifaximinRifamycinCH3

CH3

CH3CH3

CH3

CH3COO

CH3O CH3

CH3

O

OO

O

OH OH

OHOH

HN

22

CH3

CH3CH3

CH3

CH3COO

CH3O CH3

CH3

O

OO

O

OH OH

OHOH

HN

22

CH3

CH3

NN

Pimentel et al. NEJM 2011;364:22-32.Scarpignato. Digestion 2006;73(S1):13-27.

Rifamycin (Rifampin): Tb, Leprosy, streptococci, enterococci, staphylococci, Neisseria spp. and Enterobacteriaceae

FDA-approved uses of Rifaximin: Traveler’s diarrhea and hepatic encephalopathyTarget 1&2 study for IBS published in NEJMTarget 3 study fully enrolled 11/15/13EMEA – includes SIBO

Antibiotic Rx for SIBO

Shah. Aliment Pharmacol Ther 2013;38:925-34.

• 1356 articles reviewed, 10 met incl. criteria

• Rifaximin most commonly studied (8 studies)

• LBT normalization rate of 49.5% (Efficacy varied by antibiotic dose)

• Clinical response in 6 studies correlated with LBT normalization (SIBO eradication)

Di Stefano. Aliment Pharmacol Ther 2000;15:1001-8.

1 week course for H2+ LBT

Rifaximin properties: benefits

Non-systemic (<0.4%) (97% fecal excretion)

Gram-pos & neg; aerobes & anaerobes

Bile > water soluble – kills more bacteria in the small intestine than colon

Kills C. difficile

Huang DB, DuPont HJ. J Infection 2005;50:97-106.

Rifaximin resistance profile

Resistance Not plasmid-mediated Mutant resistant gut bacteria exhibit reduced

viability

No clinically relevant resistance 3 IBS-SIBO retreatment studies Re-Rx in 2 – 7 courses: successful

(83-100%; 1 - 5 year follow up)

Pimentel et al. Dig Dis Sci 2011;56:2067-72. Weinstock. Dig Dis Sci 2011;56:3389-90.

Yang. Dig Dis Sci 2008.

SIBO in rosacea: LBT+ prevalence

Parodi et al. Am J Gastroenterol 2008;6:759-764.Weinstock, Steinhoff. J Am Acad Dermatol 2013;68:875-6.

Weinstock. EMR review of records 2008-2013.

• Genoa, Italy: 46% of 113 consecutive rosacea clinic pts

• St. Louis, MO: 51% of 63 consecutive GI clinic pts with rosacea

• St. Louis, MO: 66% of 176 consecutive GI clinic pts with rosacea (incl. CH4+ pts)

False positive LBT: Controls

Parodi et al. Am J Gastroenterol 2008;6:759-764.Weinstock, Steinhoff. J Am Acad Dermatol 2013;68:875-6.

• Genoa, Italy: 3/60 age matched controls

• St. Louis, MO: 3/30 healthy controls

(Lactulose gets to colon faster causes FP)

Rifaximin for rosacea: 1st study

Parodi et al. Am J Gastroenterol 2008;6:759-764.

• N=113 pts seen in Rosacea Clinic

• 83 F, 31 M, age 52

• 52/113 (46%) LBT+

• 24/113 H.p.+ (7 had SIBO)

• 7 pts treated for H.p. 1 mo after SIBO Rx (clinical response occurred with SIBO Rx)

• GI sx response analyzed

Rifaximin for rosacea

Parodi et al. Am J Gastroenterol 2008;6:759-764.

• N = 52 LBT+ (H2 excretion)

• Rifaximin 1200 mg/d/10d vs. Placebo

• Randomized, blinded only to pts

• IGA scoring

• 2 dermatologists (Kappa = 0.97)

• Additional studies

• Cross-over for placebo group

• Open label used for SIBO-negative pts

• Subtype rosacea evaluated

Randomized study results

Parodi et al. Am J Gastroenterol 2008;6:759-764.

• Rifaximin normalized LBT in 28/32

• 71% cleared rosacea (GA score 0)

• 21% marked impr. (GA score 1)

• Placebo 2/20 worsened, rest unchg.

• GI sx sig. decreased with rifaximin

Courtesy of V. Savarino: Paroldi et al. Clin Gastroenterol Hepatol 2008;6;759-6.

Before & 1 mo after 1200 mg/d/10d rifaximin

Before & 1 mo after 1200 mg/d/10d rifaximin

Note periocular and cheek improvement

Courtesy of V. Savarino: Paroldi et al. Clin Gastroenterol Hepatol 2008;6;759-64.

Additional study results

Parodi et al. Am J Gastroenterol 2008;6:759-764.

• X-over: placebo group treated open-label

• 17/20 LBT normalized• 15 of the 17 had rosacea cleared

• 45/52 total eradication with rifaximin

• 35/45 cleared• Improvement maintained in 96% at 9 mo• 2 w pap/pust returned & Re-Rx worked

• LBT- group treated (see next)

Parodi et al. Am J Gastroenterol 2008;6:759-764.Rifaximin 1200 mg/d/10d

(N=32) (N=20)

Rifaximin for subtypes

Parodi et al. Am J Gastroenterol 2008;6:759-764.

Flush (2) 2 2 2

Fl/Erythosis (27) 0 - -

Papules (8) 6 5 4

Fl/Pap (34) 11 9 9

Fl/Ery/Pap (8) 7 6 3

Pap/Pustules (7) 4 4 4

Fl/Pap/Pust (16) 13 11 8

All four types (11)

9 8 5

Patient type (N) SIBO positive

Eradicated(LBT better)

Rosacea cleared

Pap/Pust groups had SIBO > non P/P (p<0.001)

Parodi study: critisms

• Baseline mean IGA not stated – delta not shown

• All sub-types included – Pust. +/- pap. was most impt to include (84/113 had

one or both)

• Study not blinded to physicians– 2 independent scores performed with high Kappa

• LBT used for SIBO Dx– Potential for more false+– Less invasive than jejunal aspiration

Second rifaximin study: methane

Parodi. UEGS. Abstract 2008.

• 15 H2+ & 15 CH4+ rosacea pts

• Rx #1: rifaximin• H2 pts - most responded • CH4 pts - little or no improvement

• Rx #2: metronidazole • CH4 pts - majority with complete or significant

clearance

(Note: need for dual therapy in IBS-methane pts)

Rifaximin for rosacea: St. Louis

Weinstock, Steinhoff. J Am Acad Dermatol 2013;68:875-6.

• N=63 pts (59 from screening colonoscopy)

• Dx by dermatolgist in 57; ETR in 50, PP in 9, refractory ocular in 4 (3 had E)

• Most did not have GI sx

• 32/63 pts (51%) had LBT+ vs. 3/30 controls (RR, 5.0; 95% CI, 1.7-15.1; P<0.001)

• 28 LBT+ pts given rifaximin 1200 mg/d/10d

• Limitations: open-label, self-assessment by questionnaire and photos by pts

Improvement: self-assessed

Weinstock, Steinhoff. J Am Acad Dermatol 2013;68:875-6.

Cleared/marked Moderate Mild Unchanged0

5

10

15

20

25

30

35

40

45

50

% Responders

46%

25%

11%

18%

Cleared Moderate Mild Unchanged or Marked

Before & 1 mo after rifaximin 1200 mg/d/10d

Significant change in nose & pruritic rash over right eyebrow – patient seen 1 year later & both areas were clear

Before & 1 mo after rifaximin 1200 mg/d/10d

Post-infectious ocular rosacea: 1 mo after rifaximin 1200/mg/day/10d

Ocular rosacea

Subsequent patient experience

Higher dose to match IBS studies and additional Rx for complex pts: • Rifaximin 550 mg TID for 14 days• Comprehensive post-SIBO Rx for

complex patients

Before & 5 wk after rifaximin 1650/mg/d/14d

Eyes, RLSfatigue,memory,and nail strengthImproved.

Case 2

Before & 1 mo after rifaximin 1200 mg/d/10d**

**Pi-IBS and rosacea (worsened after colon cancer resection)

Before & 1 mo after rifaximin 1650 mg/d/14d1.25 yrs after first treatment

Before & 1 mo after rifaximin 1650mg/d/14d

(Failing Oracea, Metrogel, Protopic)

2 mo after end of rifaximin

Less redness on cheek, nose, temple and beard area

Forehead papules: rifaximin 1650 mg/d/14d

1 mo later: reduction of papules

Before & 3 mo after rifaximin 1650/mg/d/30d

Facial rosacea study: 2014

• Prospective, R, DB, X-O study

• PPR pts at UCSF

• Rifaximin 1650 mg/d/14d vs. placebo (regardless of LBT test result – blinded)

• Rosacea-SIBO diet for all subjects

• IGA scoring and masked photographs of face over 8 wks

Steinhoff, Weinstock

Ocular surface disease (OSD)

• Dry eye• Aqueous deficiency

• Meibomian gland dysfunction • Lipid deficiency: ocular rosacea

• Eye lash loss• Tearing disorders• Corneal abrasions

• Facial rosacea & ocular rosacea• 4% – 58% concordance

Rifaximin 1650/mg/day/14d: Day 0 & Day 14

Less edema, redness and foreign body symptoms after Rx

Rifaximin 1650/mg/day/14d: Day 0 & Day 14

Less injection of conjunctiva, decreased lid margin inflm, no symptoms

2 wks after 2 wks rifaximin 1650/d/14d

Ocular rosacea study: 2014 • Prospective study over 8 wks

• Rifaximin 1650 mg/d/14d for all subjects Blinded to LBT test result

• Rosacea-SIBO diet for all subjects

• Standardized IGA ocular grading and photographs of eyes and face

Berdy, Weinstock, Steinhoff

Rosacea and other SIBO diseases/disorders

Scleroderma: case study• Sclerodactyly, Raynaud’s,

GERD, oral changes

• GI SIBO sx– Bloating – Fatigue– Fe & B12 def

• New SIBO sx– RLS 1

– Rosacea of face (not reported)

(Oc. Ros. - 45 SSc pts: 49% dry eyes, 40% blepharitis 2)

1). Sleep Med 2002;3:341-5. 2). Arch Clin Exp Ophthalmol 2012;250:1051-6.

Scleroderma pt4 wks after 2 wks Xifaxan and metronidazole (failed doxycyline)

Rosacea: nose and cheeks much betterRLS: completely better

Diabetes

• Meibomian gland dysfunction study in a general population

• N=619 people with and without eye sx

• Asx MGD in 22%

• Diabetes OR = 2.2

2013 study:Viso et al. Invest Opthalmol Vis Sci 2012;53:2601-6.

Spoendlin et al. J Invest Dermatol 2013;133:2790-3.

Rheumatoid arthritis

• MGD study (cont.)

• Sx MGD in 8.6% of population

• Facial rosacea pts: OR = 3.5

• Rheumatoid arthritis pts: OR = 16.5

Keratoconjunctivitis common eye disease in RA

RA seen in some neurogenic rosacea ptsViso et al. Invest Opthalmol Vis Sci 2012;53:2601-6.

Hamideh. Semin Arthritis Rheum 2001;30:217-41.Scharshmidt et al. Arch Dermatol 2011;147:123-6.

Crohn’s disease– Incidence of 5/60 consecutive CD clinic pts

– 3 active rosacea: treated with rifaximin: 1 partial and 2 complete response

– 2 not active (for both conditions)

– Cases included:• 60 y.o. F w 40 yr ileitis on no Rx

CD flares assoc w nasal rosacea – Rx - cleared• 46 y.o. M 26 yr CD s/p IC resection on 6-MP

CD flares assoc w facial rosacea – Rx - cleared• 32 y.o. F – see next

Weinstock. J Clin Gastroenterol 2011; 45:295-297.

Case 3: 32 y.o. WF with CD and rosacea

Effect after 2 wks rifaximin

1200/mg/d/10 d

32 y.o. WF with CD failing Rx.

Off all meds.

Subsequent effect of 8 wks biologic therapy (adalimulab)

Celiac disease

• Celiac disease/SB disease

– 20 of 60 rosacea pts had abnormal jejunal Bx

– 4/20 were typical for celiac disease

Possibities:• IL-8 and celiac • Primary effects of SIBO in jejunum

Watson et al. Lancet 1965;7402:48-50.

Parkinson’s disease

• 70 PD pts, 22 controls – Sebumetry, corneometry, pH

• 51% hyperhidrosis (low pH)• 32% cold/hot flush*• 19% rosacea*• 19% seborrhoea on forehead

• MOA: “possible loss of vasostability d/t autonomic dysregulation in skin”

Fischer et al. J Neural Transm 2001;108:205-13.

Parkinson’s disease

• Alpha-synuclein damages enteric neurons and reduces GI motility (prior to CNS Sx)• Prevalence of SIBO (LBT+)

– PD (33) vs. controls (30): 55% vs. 20%; P=0.01– PD (48) vs. controls (36): 54% vs. 8%; P<0.0001–

– - SIBO Rx helped neuro sx

Paillusson et al. J Neurochem 2013;125:512-7. Gabrielli et al. Mov Disord 2011;265:889-92.

Davies et al. Parkinson's disease. Mov Disord 2013;28:1241-9.  

Steatohepatitis and rosacea?

Steatohepatitis

• Liver expert poll: rosacea seen in NASH & ETOH, not viral or autoimmune hepatitis (Poordad, Bacon, Tetri)

• Steatohepatitis (w/ & w/o ETOH)– SIBO (78% LBT+ in NASH)

– LPS and IL-8

– IL-17 ---- increases VEGF (leads to angiogenesis)

Bastard et al. Eur Cytokine Netw 2006;17:4-12. Shanab. Dig Dis Sci 2011;56:1524-34. Chander Roland B, J Clin Gastroenterol 2013;47:888-93.

Baudouin. J Fr Ophtalmol.2007;30:239-46.

Obesity and inflammation

• Cytokines– Incr. T-cells, TNF-alpha, IL-6

• Dysbiosis– IBS & steatohepatitis link– Methane-obesity link

• Fat absorption linked to histamine release (in rats)

Bastard et al. Eur Cytokine Netw 2006;17:4-12. Scalera. World J Gastroenterol 2013;19:5402-5420. Basseri et al. Gastroenterol Hepatol 2012;8:22-8. Ji et al. Am J Phys G L Phys 2013;304:G732-40.

Alcohol abuse

• Alcohol – flush• 1 ref for rosacea

(not controlled)

Bernstein JE, Soltani K. Br J Dermatol 1982;107:59-61.Kostović K, Lipozencić J. Acta Dermatovenerol Croat 2004;12:181-90.

Theoretical links in pathophysiogy

Rosacea? Upregulates local immune & inflm.

? Increases dermal vascular permeability

? Neurogenic inflam. or incr. in collagenase and bacterial virulence*

? Food triggers

SIBOSystemic IL-8 (or IL-6/TNF, IL-18 in NASH)

LPS, IL-8 and integrin B-7

Systemic substance P

FODMAPs/bacterial activityHistamine foods and mast cells *Miljouin. PLoS One 2013

Summary

• Diseases and SIBO occurs after enteric infections

• SIBO causes systemic inflammation

• Rifaximin helps “Rosacea-SIBO”

Altered local

immunity

SIBO Inflammation

& immunity

Cutaneous disorders

Rosacea

Multiple disorders & triggers

Rosacea

Interacting disorders

SIBO TLR2 &

calthelicin

Environmental Food

Triggers

Vascular and neural disorders

Inflammation

Mites & bacteria

Activated OGFr

Endothelial cell barrier maintained

Lymphocytesproduction controlled

Opioid growth factor & receptor

= Met-enkephalin (endorphin)

Singleton. Am J Respir Cell Mol Biol 2007;37:222-31.Zagon. Immunobiology. 2011;216:579-90.

Activated OGFr

SRC and pY production leads to endothelial cell barrier disruption

(Integrin could worsen net effect)

LPS & OGFr – role in rosacea?

Decreased OGFrActivityShort-term

Cells perceive OGFr reduction

Potential Rx for LPS-induced inflam: Naltrexone binds to OGFr

Activated OGFr

Animal studies:

Decreased T- and B-cell activity and less permeability

(Decreased neovascularity in cornea – rats)

Naltrexone & OGFr

Zagon. Arch Ophthalmol 2008;126:501-6.

Role of Mast Cells in IBS

Abdominal pain and severity correlated with the number of mast cells <5µm

Barbara. Gastroenterology. 2004;126:3.

Normal IBS

Proximity to nerves

Elevated tryptase and histamine

Rosacea food triggers

• Direct • Hot temperature• Histamine foods

• Indirect• FODMAPs• Spicy food

• History • 1926 – Carbohydrate intolerance (Kendall)• 1966 – GI sx but Nl mucosal enzyme activity• 2008-13 – SIBO link and risks of FODMAPs

Food triggers: GI perspective

• Spicy food• Increase capsaicin

• Hot drinks• Release vasoactive proteins

• Histamine foods• Activation of mast cells

• FODMAP foods• Increase fermentation & inflammation• Substance P• Hydrogen sulfide

• Spicy food (45%)• Hot drinks (36%)• Histamine foods

– Red wine– Aged cheese– Yogurt– Beer– Bacon

• Other triggers– Chocolate– Vanilla– Soy sauce– Yeast extract– Vinegar– Liver

Wilkin J, National Rosacea Society Survey.

• Alcohol (52%) • Fruit (13%)

– Citrus fruits – Red plums– Raisins & figs– Tomatoes – Bananas

• Dairy (8%)– Aged cheese– Yogurt

• Vegetables– Broad-leaf beans & pods– Avocado– Eggplant– Spinach

General principles of SIBO RxD

iag

no

sis

Lactulose breath test

vs.

History

No

n-a

bs

orb

ed

AB

x

Rifaximin

Co

mp

reh

en

siv

e R

x

Improve motility

Restore permeability

Reduce inflammation

Weinstock, Fern, Thyssen, Todorczuk. Am J Gastroenterol 2006;110:A1124

Repeat rifaximin Rx for IBS

N in study

N repeat Rx 1st response Re-treatment responses

169 1 – 6 75%

1) 54/65; 2) 38/40; 3) 17/18

had 100% response

99 1 – 7 74%

49 pts re-Rx avg 2.2x over 3.8 yrs had 100% response; 9% needed intermittent rifaximin since prokinetic Rx failed

84 1 – 2 69%1) 16/16; 2) 4/4

had 100% response

Pimentel. Dig Dis Sci 2011.Weinstock. Dig Dis Sci 2011.

Yang, Dig Dis Sci 2008.

H. pylori controversy

• Local gastric infection with systemic immune changes

• Cag-A more virulent – prevalent in Poland & China

• A possible “coincidence” - H. pylori Rx also treats SIBO and also rosacea – which one explains the phenomenon observed in H.p. pts?

H. pylori: “plausible study”• N=60, 31-72 y.o. Polish pts with P/P/E/F

• 60 age- & gender-matched NUD pts w/o rosacea

• Hp prevalence in rosacea 88% vs. 65% in NUD

• Rosacea pts: 67% were cytotoxin-associated gene A (CAG-A) positive vs. 32% of controls pts

• OCM Rx: 51/53 rosacea pts became Hp-

• Within 2-4 wks rosacea disappeared in 51, markedly declined in 1 and remained unchanged in 1 subject

• Rx decreased IL-8 (65%) and TNF-alpha (72%)Szlachcic et al J Physiol Pharmacol. 1999;50:777-86.

Complex Regional Pain Syndrome• Reflex Sympathetic Dystrophy or Reflex Neurovascular

Dystrophy• Severe pain, swelling & changes in skin often in arm or leg• Spreads throughout the body in 92%• Neurogenic inflammation, nociceptive sensitisation

vasomotor dysfunction & aberrant response to tissue injury

Report: 2 cases with improvement with LDNChopra. Neuroimmune Pharmacol 2013;8:470-6.

Stage MGD Grade Symptoms Corneal Staining

1

+ (minimally altered expressibility and secretion quality)

None None

2++ (mildly altered expressibility and secretion quality)

Minimal to Mild None to limited

3

+++ (moderately altered expressibility and secretion quality)

Moderate Mild to moderate; mainly peripheral

4

++++ (severely altered expressibility and secretion quality)

Marked Marked; central in addition

“Plus” disease Co-existing or accompanying disorders of the ocular surface and/or eyelids

Clinical Summary of the MGD Staging Used to Guide Treatment

Geerling G, Tauber J, Baudouin C, et al. The international workshop on meibomian gland dysfunction: report of the subcommittee on management and treatment of meibomian gland dysfunction. Investigative ophthalmology & visual science. Mar 2011;52(4):2050-2064.

• N = 60 rosacea pts & 50 controls (66% F)

• Waist, BMI, glucose, CRP, lipids

• Median duration of rosacea 36 mo

• High total cholesterol (>200 mg/dL), LDL (>130 mg/dL) & high CRP levels, FHx of premature CVD and Hx smoking & ETOH > in rosacea vs. controls

• Rosacea pts may have a high risk of CVD

Duman N. J Eur Acad Dermatol Venereol. 2013 Aug 2. doi: [Epub ahead of print]

Rosacea & CV risk factors

Healthy GI microbiota

• Immune system development• Epithelial integrity• Inhibition of NF-kB activation• Anti-inflammatory metabolite production• Colonization resistance• Mucus homeostasis• Bile acid deconjugation• Lipid metabolism• Insulin resistance

Altered gut secretion & motility

Mediators• Histamine• Tryptase• Lipid mediators• Cytokines

Activating factors• Intestinal permeability• Bacteria and biproducts• Food allergies (IgE- & non-IgE-mediated)• Neuropeptides• Bile acids

Sensory neurons

CNS Stress

Pain

GI Pain

CPPS

Corticotrophin Releasing Factor

Mast Cell

Pezzone. Gastroenterology 2005;128:1953-64

Barbara. Neurogastroenterol Motil. 2006;18:6-17.

ENS

Cross talk