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

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