Transcript see the power point presentation - Specialists in Gastroenterology

Ocular Rosacea
Effect of treating small
intestinal bacterial overgrowth
Leonard Weinstock, MD
Associate Professor of Clinical Medicine
Washington University in St. Louis
Specialists in Gastroenterology
Disclosures
Speaker’s Bureau:
Salix
Actavis
Entera Health
Romark
I am a gastroenterologist
Review
• Small intestinal bacterial overgrowth
• Enteric infections lead to diseases
• Rifaximin for facial rosacea-SIBO
• Rifaximin for ocular rosacea-SIBO
Rosacea and the Gut
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Alcohol & obesity – 13th century (Chaucer)
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
Small intestinal bacterial overgrowth – 2008
Normal host prevents SIBO
Stomach
Colon bacterial balance,
integrity & immunity
0 - 1000
Mucosal
absorption
Pancreas
Colon
100,000,000,000,000
coliforms
(bacteroides, firmicutes,
bifidobacter, clostridium)
oral bacteria
(streptococcus,
lactobacillus)
Acid
Motility
Immunity
Duodenum &
Jejunum
1,000
oral bacteria
ICV
Distal ileum
100,000,000 -1,000,000,000
coliforms
Proximal ileum
10,000
oral bacteria
Mondot. Dig Dis 2013;31:278-85.
SIBO syndrome
• Definition
– >105 colony forming units/mL in jejunum
– Sx and/or signs of malabsorption
• Treatment
– 1o small bowel abnormality
– Antibiotics
– Motility
– Intestinal permeability
Gregg CR, Toakes PP. In Sleisenger and Fortran. Gastrointestinal and Liver Disease.
SIBO Syndromes
Scleroderma *
Small intestinal
pseudo-obstruction
Achlorhydria *
Diabetes *
Pancreatic
insufficiency *
Radiation enteritis
Jejunal diverticulosis
Immunodeficiency:
CLL, IgA def.,
T-cell def.
* Associated w rosacea
Billroth, Blind-loop
ICV resect., J-pouch
New SIBO Syndromes
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Crohn’s dis. *
Celiac dis. *
Irritable bowel synd. *
Chronic liver dis. *
• Restless legs synd.
• Rosacea
• Parkinson’s dis. *
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Renal failure
Hypothyroidism
Acromegaly
Post-chemotherapy
Fibromyalgia
Rheumatoid arthritis *
Interstitial cystitis
Chronic prostatitis
* Associated with rosacea
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.
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.
Post-infectious IBS &
Associated Syndromes
Infection
in gut
Motility
leads to
SIBO
Genetic phenotype (low IL-10) for IBS
Pi-IBS,
Rosacea,
FMS, RLS,
CPPS
42 F s/p dysentery
followed by:
– E/F/Phyma
& ocular rosacea
– IBS-c
– Cognitive dysfx
– Fatigue
– RLS
45
40
35
30
25
H2
20
CH4
15
Dx of SIBO by LBT
10
5
0
0
30
45
60
75
90
Rifaximin 1650-mg/d/14d: Day 0 and Day 45
Eyes, RLS,
fatigue, &
memory
Improved
Inflammation in SIBO
• Interleukins – IL 1ß, 6, 8**, 12
• TNF-α
• LPS
• T- and B-lymphocytes
• Mast cells** infiltration in gut
• Increased histamine, tryptase and serotonin
• Substance P
•
** In
rosacea
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.
SIBO in Rosacea: Prevalence (LBT+)
• 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
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.
Rifaximin for Rosacea: Italy
• 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% unchanged
Parodi et al. Am J Gastroenterol 2008;6:759-764.
Rifaximin 1200-mg/d/10d: Day 0 & 1 mo later
Courtesy of V. Savarino:
Paroldi et al. Clin Gastroenterol Hepatol 2008;6;759-6.
Rifaximin 1200-mg/d/10d: Day 0 & 1 mo later
Courtesy of V. Savarino:
Paroldi et al. Clin Gastroenterol Hepatol 2008;6;759-64.
Rifaximin for Rosacea: St. Louis
• 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 of 32 LBT+ pts were treated
• Rifaximin 1200-mg/d/10d open label
Weinstock, Steinhoff. J Am Acad Dermatol 2013;68:875-6.
Improvement: self-assessed
% Responders
50
45
40
46%
35
30
25
25%
20
15
18%
10
11%
5
0
Cleared/marked
Cleared
or Marked
Moderate
Moderate
Mild
Mild
Unchanged
Unchanged
Weinstock, Steinhoff. J Am Acad Dermatol 2013;68:875-6.
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
Rifaximin 1200-mg/d/10d: Day 0 & 1 mo later
Improvement: self-assessed
All 4 of those with
ocular disease
improved
Weinstock, Steinhoff. J Am Acad Dermatol 2013;68:875-6.
Ocular Rosacea
SIBO 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 2016
Ocular Rosacea
SIBO Study
• N=24 (21F/3M), age 59
• Facial rosacea in 4
• LBT+ in 9/24 (38%)
• GI sx in 63% LBT+ vs. 33% LBTWeinstock 2016
Ocular Rosacea
SIBO Study
Global assessment in 7 pts
4 marked improvement
1 moderate improvement
2 mild improvement
» Two did not take Rx
• Insurance denied the prescription in one subject
• One subject was lost was to follow up
Weinstock 2016
Rifaximin 1200-mg/day/10d: Day 0 & Day 30
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
Rifaximin 1650-mg/d/14d: Day 0 & Day 30
Rifaximin for Ocular Rosacea
Conclusions
• Rifaximin 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 glands
Standard of Care Rx
• Increase ambient humidity
• Omega-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)
Ocular Rosacea
Prevalence: up to 58% of rosacea pts
(more in older age group)
Symptoms: dry eyes, foreign body sensation,
burning, decreased tears, watering, pain,
photosensitivity
Signs: eyelid erythema and vascularization,
lymphedema, blepharitis, and corneal ulcers
Rosacea
Rosacea
Multiple disorders
& triggers
Interacting
disorders
Altered local
immunity
Vascular and
neural disorders
Cutaneous
disorders
Inflammation
SIBO
TLR2 &
calthelicin
Mites &
bacteria
Inflammation
& immunity
SIBO
Triggers
Environmental
Food
Rifaximin for rosacea: 1st study
• 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
Parodi et al. Am J Gastroenterol 2008;6:759-764.
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 for rosacea
• 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
Parodi et al. Am J Gastroenterol 2008;6:759-764.
Additional study results
• 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.
(N=32)
Rifaximin 1200 mg/d/10d
(N=20)
Parodi et al. Am J Gastroenterol 2008;6:759-764.
Rifaximin for subtypes
Patient type (N)
SIBO
positive
Eradicated
(LBT better)
Rosacea
cleared
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
Pap/Pust groups had SIBO > non P/P (p<0.001)
Parodi et al. Am J Gastroenterol 2008;6:759-764.
Activating factors
• Intestinal permeability
Mast Cells –
in gut
• Seen with SIBO
• Bacteria and byproducts
• Food allergies (IgE- &
non-IgE-mediated)
• Neuropeptides
• Bile acids
Mediators
• Histamine
• Tryptase
• Lipid mediators
• Cytokines
? Cathelicidin
initiated skin
inflammation
Mast Cells – in skin
Could a trigger cause the bone marrow
to produce mast cells?
Muto. J Invest Dermatol. 2014; 134:2728-36
Barbara. Neurogastroenterol Motil. 2006;18:6-17.
Systemic Cytokines in Rosacea
• 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
Salamon. Przegi Lek 2008;65:371-4.
Clinical Summary of the MGD Staging Used to Guide
Treatment
Stage
1
2
3
4
“Plus” disease
MGD Grade
Symptoms
+ (minimally altered
expressibility and
None
secretion quality)
Corneal Staining
None
++ (mildly altered
expressibility and
Minimal to Mild
None to limited
secretion quality)
+++ (moderately
altered expressibility
Mild to moderate;
Moderate
and secretion
mainly peripheral
quality)
++++ (severely
altered expressibility
Marked; central in
Marked
and secretion
addition
quality)
Co-existing or accompanying disorders of the ocular surface
and/or eyelids
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.
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 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.
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.
Theoretical links in pathophysiogy
SIBO
Rosacea
Systemic IL-8
? Upregulates local
(or IL-6/TNF, IL-18 in NASH) immune & inflm.
LPS, IL-8 and integrin B-7
? Increases dermal
vascular permeability
Systemic substance P
? Neurogenic inflam. or
incr. in collagenase and
bacterial virulence*
FODMAPs/bacterial activity
Histamine foods and mast
cells
? Food triggers
*Miljouin. PLoS One 2013
Role of Mast Cells in IBS
Normal
IBS
Abdominal pain and severity
correlated with the number of
mast cells <5µm
Proximity to nerves
Elevated tryptase and
histamine
Barbara. Gastroenterology. 2004;126:3.
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
• 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
Wilkin J, National Rosacea Society Survey.
• 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
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.