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Rosacea and GI disorders
Inflammation and Dysbiosis
Leonard Weinstock, MD
Associate Professor of Clinical Medicine
Washington 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
“Post-infectious Rosacea”
“Rosacea-SIBO”
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
42 F s/p Mont. revenge
13 yrs ago followed by:
– E/F/Phyma
and ocular rosacea
– Nail disorder
–
–
–
–
IBS-c
Cognitive dysfx
Fatigue
RLS
45
– Steatohepatitis
– Type 2 DM
40
35
30
25
H2
20
CH4
15
10
5
Dx: Bacterial overgrowth
0
0
30
45
60
75
90
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
• 10 SF
• Barrier with vascular
& nerve interface
• Barrier with vascular
& nerve interface
• Bacteria (100 trillion)
• Bacteria (and mites)
• > 500 types
• Commensal
when in balance
and with normal
innate and
systemic
immunity
• > 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
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.
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 rosaceaassociated disorders
Kaposi. Pathology and Treatment of Disease of the Skin. 1895.
Textbooks and rosaceaassociated disorders
• GI disorders (dyspepsia, diarrhea, constip)
• H. pylori:
Coincidental , plausible , undecided
2, 3
4
• Parkinson’s disease
• Hormonal changes 3
• Menopause
• Migraine
1-3
• Orthostatic hypotension
• Vasoactive tumors
• HIV 4, 5
• CNS tumors 1
5
1, 2
2
2
1
1
1.
2.
3.
4.
5.
Pelle. In Fitzpatrick 2012.
Webster. In Bolognia 2008.
In McKae 2005.
Berth-Jones. In Rooks 2004.
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
70
Early rise
in H2 (or
CH4) in
SIBO
gas chromatography
Hydrogen (ppm)
60
50
40
30
20
10
0
15
30
45
60
75
90
105 120 135 150 165 180
Time (in minutes)
Normal
SIBO
• No gold standard to Dx SIBO - culture problems
• Bacteria may be in various locations in the small bowel
• Difficult to culture anaerobes
Textbook SIBO
Scleroderma *
Small intestinal
pseudo-obstruction
Achlorhydria *
Diabetes *
Pancreatic
insufficiency *
Radiation enteritis
Jejunal diverticulosis
Immunodeficiency:
CLL, IgA def.,
T-cell def.
Post-surgical Billroth, Blind-loop
anatomy: 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. *
•
•
•
•
•
•
•
•
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.
Diseases after GI infections
 Guillain-Barré syndrome
 Celiac disease
 Reactive arthritis
 Pancreatitis
 IBS – 20% recall infection first
Molecular mimicry &
autoimmune pathways
with genetic predisposition
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.
Post-infectious IBS &
associated syndromes
Infection
in gut
Motility
leads to
SIBO
Genetic phenotype (low IL-10) for IBS
Pi-IBS,
FMS, RLS,
CPPS
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
• 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.)
Riordin. Scand J Gastroenterol 1996;31:977-84.
• A-V Ab
Lin. JAMA 2004;292:852-8.
Hughes et al. Am J Gastroenterol 2013;108:1066-74.
Martinez et al. Gut 2013;62:1160-8.
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.
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
CH3
CH3
CH3COO
CH3
CH3
22
OH
OH
CH3
CH3
OH
CH3O
CH3
22
OH
OH
CH3
CH3COO
CH3
OH
OH
H
N
CH3
CH3O
OH
CH3
H
N
O
O
O
O
O
N
O
CH3 O
Rifamycin
Rifamycin (Rifampin):
Tb, Leprosy, streptococci,
enterococci, staphylococci,
Neisseria spp. and
Enterobacteriaceae
CH3
CH3 O
Rifaximin
N
CH3
FDA-approved uses of Rifaximin:
Traveler’s diarrhea and hepatic encephalopathy
Target 1&2 study for IBS published in NEJM
Target 3 study fully enrolled 11/15/13
EMEA – includes SIBO
Pimentel et al. NEJM 2011;364:22-32.
Scarpignato. Digestion 2006;73(S1):13-27.
Antibiotic Rx for SIBO
• 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)
Shah. Aliment Pharmacol Ther 2013;38:925-34.
1 week course for H2+ LBT
Di Stefano. Aliment Pharmacol Ther 2000;15:1001-8.
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
• 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)
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.
False positive LBT: Controls
• Genoa, Italy: 3/60 age matched controls
• St. Louis, MO: 3/30 healthy controls
(Lactulose gets to colon faster causes FP)
Parodi et al. Am J Gastroenterol 2008;6:759-764.
Weinstock, Steinhoff. J Am Acad Dermatol 2013;68:875-6.
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 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.
Randomized study results
• 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
Parodi et al. Am J Gastroenterol 2008;6:759-764.
Before & 1 mo after 1200 mg/d/10d rifaximin
Courtesy of V. Savarino:
Paroldi et al. Clin Gastroenterol Hepatol 2008;6;759-6.
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
• 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.
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
• 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)
Parodi. UEGS. Abstract 2008.
Rifaximin for rosacea: St. Louis
• 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
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.
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
Ocular rosacea
Post-infectious ocular rosacea:
1 mo after rifaximin 1200/mg/day/10d
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
Case 2
Eyes, RLS
fatigue,
memory,
and nail
strength
Improved.
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/14d
1.25 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
– Rosacea of face (not reported)
1
(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 pt
4 wks after 2 wks Xifaxan and
metronidazole (failed doxycyline)
Rosacea: nose and cheeks much better
RLS: 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 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.
Case 3: 32 y.o. WF with CD and rosacea
32 y.o. WF with
CD failing Rx.
Off all meds.
Effect after 2 wks
rifaximin
1200/mg/d/10 d
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
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
Summary
• Diseases and SIBO occurs after enteric
infections
• SIBO causes systemic inflammation
• Rifaximin helps “Rosacea-SIBO”
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
Opioid growth factor & receptor
= Met-enkephalin (endorphin)
Activated OGFr
Endothelial
cell barrier
maintained
Lymphocytes
production
controlled
Singleton. Am J Respir Cell Mol Biol 2007;37:222-31.
Zagon. Immunobiology. 2011;216:579-90.
LPS & OGFr – role in rosacea?
Activated OGFr
SRC and pY
production
leads to
endothelial
cell barrier
disruption
(Integrin could
worsen net
effect)
Potential Rx for LPS-induced
inflam: Naltrexone binds to OGFr
Decreased
OGFr
Activity
Short-term
Cells
perceive
OGFr
reduction
Naltrexone & OGFr
Animal studies:
Activated OGFr
Decreased Tand B-cell
activity and less
permeability
(Decreased
neovascularity in
cornea – rats)
Zagon. Arch Ophthalmol 2008;126:501-6.
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
Rifaximin
Comprehensive Rx
Lactulose
breath
test
vs.
History
Non-absorbed ABx
Diagnosis
General principles of SIBO Rx
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
1) 54/65; 2) 38/40; 3) 17/18
169
99
84
1–6
1–7
1–2
75%
had 100% response
74%
49 pts re-Rx avg 2.2x over 3.8 yrs
had 100% response;
9% needed intermittent rifaximin
since prokinetic Rx failed
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 LDN
Chopra. Neuroimmune
Pharmacol 2013;8:470-6.
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.
Rosacea & CV risk factors
• 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]
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
Mediators
Activating factors
• Intestinal permeability
Mast Cell
• Bacteria and biproducts
• Food allergies (IgE- &
non-IgE-mediated)
• Neuropeptides
• Bile acids
• Histamine
• Tryptase
• Lipid mediators
• Cytokines
ENS
Altered gut
secretion & motility
Sensory
neurons
GI Pain
CPPS
Corticotrophin
Releasing
Factor
CNS
Pain
Cross talk
Stress
Pezzone. Gastroenterology 2005;128:1953-64
Barbara. Neurogastroenterol Motil. 2006;18:6-17.