Ocular Rosacea - PowerPoint Presentation

Slide1

Ocular Rosacea Effect of treating small intestinal bacterial overgrowth

Leonard Weinstock, MD

Associate Professor

of Clinical Medicine

Washington University in St. Louis

Specialists in GastroenterologySlide2

Disclosures

Speaker’s Bureau: Salix

Actavis

Entera HealthRomark

I am a gastroenterologistSlide3

Review

Small intestinal bacterial overgrowth

Enteric infections lead to

diseases

Rifaximin for facial

rosacea-SIBO

Rifaximin

for

ocular

r

osacea-SIBOSlide4

Rosacea and the GutAlcohol & obesity – 13th century (Chaucer)Dyspepsia – 1895Food intolerance/allergies – 1926-1966Achlorhydria – 1935, 1941

Gastritis – 1941Celiac/jejunal diseases – 1965, 1970Chronic pancreatitis – 1982

H. pylori – 1990’sIBD – UC 1989; CD 2000 Small intestinal bacterial overgrowth – 2008 Slide5

Normal host prevents SIBO

Stomach0 - 1000

oral bacteria

(streptococcus,

lactobacillus)

Colon

100,000,000,000,000

coliforms

(bacteroides, firmicutes, bifidobacter, clostridium)

Distal ileum

100,000,000

-1,000,000,000

coliforms

Duodenum &

Jejunum

1,000 oral bacteria

Proximal ileum 10,000 oral bacteria

Acid

Motility

ICV

Pancreas

Mucosal

a

bsorption

Immunity

Colon bacterial balance,

integrity & immunity

Mondot

. Dig

Dis

2013;31:278-85.Slide6

SIBO syndromeDefinition>105 colony forming units/mL

in jejunum

Sx and/or signs of malabsorptionTreatment

1o

small bowel abnormality

Antibiotics

Motility

Intestinal permeability

Gregg

CR,

Toakes

PP.

In

Sleisenger

and Fortran. Gastrointestinal and Liver

Disease.Slide7

Scleroderma *

Achlorhydria

*

Small intestinal pseudo-obstruction

Diabetes

*

Pancreatic insufficiency

*

Radiation enteritis

Jejunal

diverticulosis

Immunodeficiency: CLL, IgA def., T-cell def.

*

Associated w rosacea

Billroth

, Blind-loop ICV

resect

., J-pouch

SIBO SyndromesSlide8

New SIBO SyndromesCrohn’s dis. *Celiac

dis. *Irritable

bowel synd.

*Chronic

liver

dis.

*

Restless legs

synd.

Rosacea

Parkinson’s dis.

*

*

Associated with rosacea

Renal

failureHypothyroidism

AcromegalyPost-chemotherapyFibromyalgia

Rheumatoid arthritis *Interstitial cystitisChronic 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.Slide9

Rifaximin is Ideal Antibiotic for SIBO

Non-systemic (<0.4

%)

Gram-pos & neg; aerobes &

anaerobes

Bile >

water soluble

– kills

more bacteria

in small

intestine

than colon

Kills C.

difficile

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

.Slide10

Post-infectious IBS & Associated Syndromes

Genetic phenotype (low IL-10) for IBSSlide11

42 F s/p dysentery followed by:

E/F/Phyma& ocular rosacea

IBS-c

Cognitive dysfxFatigue

RLS

Dx of SIBO by LBT Slide12

Rifaximin 1650-mg/d/14d: Day 0 and Day 45

Eyes, RLS,fatigue, &memory ImprovedSlide13

Inflammation in SIBORiordin. 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

LPS

T- and B-lymphocytes

Mast cells

**

infiltration in gut

Increased histamine,

tryptase

and serotoninSubstance P ** In rosaceaSlide14

SIBO in Rosacea: Prevalence (LBT+)

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 rosaceaSlide15

Rifaximin for Rosacea: Italy

Parodi

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

.

52 LBT+ randomized for Rx

Rif 1200-mg/d/10d vs. Placebo

Rifaximin (N=32)

71% GA score 0

21% GA score 1

Placebo (N=20)

10% worse

90% unchangedSlide16

Courtesy of V. Savarino

: Paroldi et al. Clin Gastroenterol Hepatol 2008;6;759-6.

Rifaximin 1200-mg/d/10d: Day 0 & 1 mo later Slide17

Rifaximin 1200-mg/d/10d: Day 0 & 1 mo later

Courtesy

of V.

Savarino

:

Paroldi

et al. Clin Gastroenterol

Hepatol

2008;6;759-64.Slide18

Rifaximin for Rosacea: St. LouisWeinstock, Steinhoff. J Am Acad Dermatol 2013;68:875-6

.N=63 pts

E/T

in 50, PP

in 9,

Ocular in 4 (

3 had

E)

LBT+ 32/63 (51%) vs. 3/30 (10%) controls (RR,

5.0; 95%

CI,

1.7-15.1;

P

<0.001)

28

o

f 32 LBT+ pts were treatedRifaximin 1200-mg/d/10d open labelSlide19

Improvement: self-assessedWeinstock, Steinhoff. J Am Acad Dermatol 2013;68:875-6.

46%

25%

11%

18%

Cleared Moderate Mild Unchanged

or MarkedSlide20

Rifaximin 1200-mg/d/10d: Day 0 & 1 mo later Significant change in nose & pruritic rash over right eyebrow – patient seen 1 year later & both areas were clear Slide21

Rifaximin 1200-mg/d/10d: Day 0 & 1 mo later Slide22

Improvement: self-assessedWeinstock, Steinhoff. J Am Acad Dermatol 2013;68:875-6.

All 4 of those with ocular disease improvedSlide23

Ocular RosaceaSIBO Study Methods

Refractory ocular rosacea pts referred by four ophthalmologists

Open-label, rifaximin 1650-mg/d

for 10-14 d

in LBT+

Global assessment

10

d

&

20 d after ending

rifaximin: marked

, moderate,

mild

improvement

, or unchanged

Weinstock 2016Slide24

Ocular RosaceaSIBO Study N=24 (21F/3M), age 59

Facial rosacea in 4LBT+ in 9/24 (38%)

GI

sx in 63% LBT+ vs. 33%

LBT-

Weinstock

2016

Slide25

Ocular RosaceaSIBO Study

Global assessment in 7 pts4 marked improvement1 moderate improvement

2 mild improvement

Two did not take RxInsurance denied the prescription in one subject One subject was lost was to follow

up

Weinstock

2016

Slide26

Rifaximin 1200-mg/day/10d: Day 0 & Day 30 Slide27

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

Less edema, redness and foreign body symptoms after RxSlide28

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

Less injection of conjunctiva, decreased lid margin

inflm, no symptomsSlide29

Rifaximin 1650-mg/d/14d: Day 0 & Day 30Slide30

Rifaximin for Ocular Rosacea ConclusionsRifaximin led to improvement in this small open-label study

Dysregulation of innate immune system d/t GI inflammation could increase systemic cytokines and microbial antigens/antibodies

affecting eyelids and meimobian glandsSlide31
Slide32

Standard of Care RxIncrease ambient humidityO

mega-3 fatty acid

Eyelid hygiene: eyelid warming then massage and

expression of MG secretions Topical

emollient lubricant or liposomal spray

Topical

azithromycin

Bedtime lubricant

Oral

tetracycline

or doxycycline

Anti-inflammatory therapy

(cyclosporine)Slide33

Ocular RosaceaPrevalence: up to 58% of rosacea pts (more in older age group)

Symptoms: dry eyes, foreign body sensation, burning, decreased tears, watering, pain, photosensitivitySigns: eyelid erythema and vascularization, lymphedema, blepharitis, and corneal ulcersSlide34

Altered local

immunity

SIBO

Inflammation

& immunity

Cutaneous disorders

Rosacea

Multiple disorders & triggers

Rosacea

Interacting disorders

SIBO

TLR2 &

calthelicin

Environmental

Food

Triggers

Vascular and

n

eural disorders

Inflammation

Mites & bacteriaSlide35

Rifaximin for rosacea: 1st study

Parodi

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

.

N=113 pts seen in

R

osacea

C

linic

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 analyzedSlide36

Rifaximin properties: benefits

Non-systemic (<0.4

%)

(97%

fecal excretion)

G

ram-pos & neg; aerobes &

anaerobes

Bile >

water soluble

– kills

more bacteria in the

small

intestine

than colon

Kills C.

difficileHuang DB, DuPont HJ. J Infection 2005;50:97-106.Slide37

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 evaluatedSlide38

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)Slide39

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

(N=32)(N=20)Slide40

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

54Fl/Pap (34)1199Fl/Ery/Pap (8)

763Pap/Pustules (7)44

4Fl/Pap/Pust (16)13118All four types (11)9

85Patient type (N)SIBO positiveEradicated(LBT better)

Rosacea cleared

Pap/Pust

groups had SIBO > non P/P (p<0.001)Slide41

Mediators

Histamine

Tryptase

Lipid mediators

Cytokines

?

Cathelicidin

initiated skin

inflammation

Activating factors

Intestinal

permeability

Seen with SIBO Bacteria and byproducts Food allergies (IgE- & non-IgE-mediated) Neuropeptides Bile acids

Mast Cells – in gut

Muto. J Invest Dermatol. 2014; 134:2728-36Barbara. Neurogastroenterol Motil. 2006;18:6-17.

Mast

Cells – in skin

Could a trigger cause the bone marrow

to produce mast cells?Slide42

Systemic Cytokines in RosaceaSalamon. 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 measuredSlide43
Slide44

StageMGD GradeSymptomsCorneal Staining1+ (minimally altered

expressibility and secretion quality)NoneNone

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” diseaseCo-existing or accompanying disorders of the ocular surface and/or eyelidsClinical 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.Slide45

DiabetesMeibomian 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

. Slide46

Rheumatoid arthritisMGD study (cont.)Sx MGD in 8.6% of population

Facial rosacea pts: OR = 3.5Rheumatoid arthritis pts: OR = 16.5

Keratoconjunctivitis

common eye disease in RA RA seen in some neurogenic rosacea pts

Viso

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.Slide47

Crohn’s diseaseIncidence of 5/60 consecutive CD clinic pts3 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.Slide48

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-7Systemic substance P

FODMAPs/bacterial activity

Histamine foods and mast cells

*

Miljouin.

PLoS One 2013Slide49

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 histamineSlide50

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 Slide51

Food triggers: GI perspectiveSpicy foodIncrease capsaicinHot drinks

Release vasoactive

proteins

Histamine foods

Activation of mast cells

FODMAP foods

Increase fermentation & inflammation

Substance P

Hydrogen sulfideSlide52

Spicy food (45%)Hot drinks (36%)Histamine foodsRed wineAged cheese

YogurtBeerBacon

Other triggersChocolate

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 cheeseYogurtVegetablesBroad-leaf beans & podsAvocado

EggplantSpinachSlide53

H. pylori controversy

Local gastric infection with systemic immune changesCag-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?Slide54

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.