Presentation on theme: "Rosacea and GI disorders Inflammation and Dysbiosis Leonard Weinstock, MD Associate Professor of Clinical Medicine Washington University in St. Louis Specialists."— Presentation transcript:

1 Rosacea and GI disorders Inflammation and Dysbiosis Leonard Weinstock, MD Associate Professor of Clinical Medicine Washington University in St. Louis Specialists in Gastroenterology



2 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



3 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”



4 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 –Steatohepatitis –Type 2 DM Dx: Bacterial overgrowth Dx: Bacterial overgrowth



5 Review Gut microbiomeGut microbiome History of rosacea & gutHistory of rosacea & gut Small intestinal bacterial overgrowthSmall intestinal bacterial overgrowth Enteric infections lead to diseasesEnteric infections lead to diseases Antibiotic Rx for Rosacea-SIBOAntibiotic Rx for Rosacea-SIBO Additional SIBO diseases and rosaceaAdditional SIBO diseases and rosacea Theories for shared pathophysiologyTheories for shared pathophysiology



6 Gut vs. skin 100 SF100 SF Barrier with vascular & nerve interfaceBarrier with vascular & nerve interface Bacteria (100 trillion)Bacteria (100 trillion) > 500 types> 500 types Commensal when in balance and with normal innate and systemic immunityCommensal when in balance and with normal innate and systemic immunity 10 SF10 SF Barrier with vascular & nerve interfaceBarrier with vascular & nerve interface Bacteria (and mites)Bacteria (and mites) > 200 types> 200 types Non-invasive when in balance and with normal innate and systemic immunityNon-invasive when in balance and with normal innate and systemic immunity



7 Gut + microbiome > skin + spleen Largest immune system



8 Normal host prevents dysbiosis Stomach 0 - 1000 oral bacteria (streptococcus, lactobacillus) lactobacillus) Colon100,000,000,000,000coliforms (bacteroides, firmicutes, bifidobacter, clostridium) Distal ileum 100,000,000 -1,000,000,000 coliforms Duodenum & Duodenum & Jejunum Jejunum 1,000 1,000 oral bacteria oral bacteria Proximal ileum 10,000 oral bacteria oral bacteria Acid Motility ICV Pancreas Mucosal absorption Immunity Colon bacterial balance, integrity & immunity Mondot. Dig Dis 2013;31:278-85.



9 Effects of dysbiosis Abnormal anatomyAbnormal anatomy –Leaky tight-junctions --- incr. intestinal permeability --- incr. intestinal permeability –Thinner lamina propria, shallow crypts –Abnormal Peyer’s patches, fewer plasma cells Immune disorders:Immune disorders: –Altered cytokine profile –Altered innate immune response (Th2 to Th1, IL-17) –Diseases: atopy, diabetes, obesity, autoimmune



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



11 History of rosacea and the gut Alcohol & obesity – 13 th 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



12 Early text and rosacea- associated disorders Kaposi. Pathology and Treatment of Disease of the Skin. 1895.



13 Textbooks and rosacea- associated disorders GI disorders (dyspepsia, diarrhea, constip) 1 GI disorders (dyspepsia, diarrhea, constip) 1 H. pylori: H. pylori: Coincidental 2, 3, plausible 4, undecided 5 Parkinson’s disease 1, 2 Parkinson’s disease 1, 2 Hormonal changes 3 Hormonal changes 3 Menopause 2 Menopause 2 M igraine 1-3 M igraine 1-3 Orthostatic hypotension 1 Orthostatic hypotension 1 Vasoactive tumors 2 Vasoactive tumors 2 HIV 4, 5 HIV 4, 5 CNS tumors 1 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.



14 Small intestinal bacterial overgrowth and rosacea Small intestinal bacterial overgrowth and rosacea First report in 2008



15 SIBO syndrome DefinitionDefinition –>10 5 colony forming units/mL in jejunum –Sx and/or signs of malabsorption Treat 1 o small bowel abnormalityTreat 1 o small bowel abnormality –“Often impractical” AntibioticsAntibiotics –Absorption and resistance concerns Motility drugsMotility drugs –Limited medications Intestinal permeabilityIntestinal permeability –Not addressed Gregg CR, Toakes PP. In Sleisenger and Fortran. Gastrointestinal and Liver Disease.



16 Lactulose breath test gas chromatography No gold standard to Dx SIBO - culture problemsNo gold standard to Dx SIBO - culture problems Bacteria may be in various locations in the small bowelBacteria may be in various locations in the small bowel Difficult to culture anaerobesDifficult to culture anaerobes Early rise in H2 (or CH4) in SIBO



17 Textbook SIBO Scleroderma * Scleroderma * Achlorhydria * Achlorhydria * Small intestinal pseudo-obstruction Small intestinal pseudo-obstruction Diabetes * Diabetes * Pancreatic insufficiency * Radiation enteritis Radiation enteritis Jejunal diverticulosis Jejunal diverticulosis Immunodeficiency: CLL, IgA def., T-cell def. Immunodeficiency: CLL, IgA def., T-cell def. Post-surgical anatomy: Billroth, Blind-loop ICV resect., J-pouch Billroth, Blind-loop ICV resect., J-pouch



18 SIBO – full blown SymptomsSymptoms PainPain BloatingBloating DiarrheaDiarrhea Foul flatusFoul flatus WeaknessWeakness Weight lossWeight loss Signs and LabsSigns and Labs EdemaEdema AnemiaAnemia CachexiaCachexia Iron def.Iron def. Vitamin def.Vitamin def. Nutrient def.Nutrient def.



19 “New” SIBO Crohn’s dis. *Crohn’s dis. * Celiac dis. *Celiac dis. * Irritable bowel synd. *Irritable bowel synd. * Chronic liver dis. *Chronic liver dis. * Restless legs synd.Restless legs synd. RosaceaRosacea Parkinson’s dis. *Parkinson’s dis. * * Associated with rosacea Renal failureRenal failure HypothyroidismHypothyroidism AcromegalyAcromegaly Post-chemotherapyPost-chemotherapy FibromyalgiaFibromyalgia Rheumatoid arthritis *Rheumatoid arthritis * Interstitial cystitisInterstitial cystitis Chronic prostatitisChronic 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.



20 Diseases after GI infections 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 pathways with genetic predisposition



21 Post-infectious IBS & associated syndromes Infection in gut Motility leads to SIBO Pi-IBS, FMS, RLS, CPPS Genetic phenotype (low IL-10) for IBS



22 Pi-IBS 7 studies/2056 people: incidence 7-30%7 studies/2056 people: incidence 7-30% Duration: 50-100% life-long (2 studies)Duration: 50-100% life-long (2 studies) Pathophysiology:Pathophysiology: –Weak MMC leads to SIBO –Rat model: Camphylobacter caused SIBO in 27% –Anti-vinculin antibody studies Rats AVA led to loss of myenteric nervesRats AVA led to loss of myenteric nerves Patients with Pi-IBS have AVAPatients with Pi-IBS have AVA Pimentel 2004, 2011, 2013



23 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: 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.



24 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 Interleukins – IL 1ß, 6, 8**, 12 TNF-α (inflm. & incr. intestinal perm.) 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 seratoninIncreased histamine, tryptase and seratonin Substance P (neuropeptide) Integrin Beta-7 T-lymphocytes (incr. vascular perm.)Integrin Beta-7 T-lymphocytes (incr. vascular perm.) A-V AbA-V Ab



25 Systemic cytokines in rosacea Salamon. Przegi Lek 2008;65:371-4. 60 rosacea pts vs. 25 controls60 rosacea pts vs. 25 controls IL-18: 163 vs. 16 pg/ml (P<0.01)IL-18: 163 vs. 16 pg/ml (P<0.01) IL-6 lower in rosaceaIL-6 lower in rosacea TNF-alpha numerically higherTNF-alpha numerically higher IL-8 not measuredIL-8 not measured



26 Changing roles of antibiotic Rx 1950’s: Tetracycline 1950’s: Tetracycline 2000: low dose doxycycline 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) Antibiotic effect on stratum corneum tryptic enzymes (SCTEs) 2008: rifaximin for rosacea-SIBO 2008: rifaximin for rosacea-SIBO Parodi et al. Am J Gastroenterol 2008;6:759-764.



27 Rifaximin – semi-sythetic RifaximinRifamycin CH 3 CH 3 COO CH 3 O CH 3 O O O O OH HNHN 22 CH 3 CH 3 COO CH 3 O CH 3 O O O O OH HNHN 22 CH 3 N N 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 encephalopathy Target 1&2 study for IBS published in NEJM Target 3 study fully enrolled 11/15/13 EMEA – includes SIBO



28 Antibiotic Rx for SIBO Shah. Aliment Pharmacol Ther 2013;38:925-34. 1356 articles reviewed, 10 met incl. criteria1356 articles reviewed, 10 met incl. criteria Rifaximin most commonly studied (8 studies)Rifaximin most commonly studied (8 studies) LBT normalization rate of 49.5% (Efficacy varied by antibiotic dose)LBT normalization rate of 49.5% (Efficacy varied by antibiotic dose) Clinical response in 6 studies correlated with LBT normalization (SIBO eradication)Clinical response in 6 studies correlated with LBT normalization (SIBO eradication)



29 Di Stefano. Aliment Pharmacol Ther 2000;15:1001-8. 1 week course for H2+ LBT



30 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.



31 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.



32 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 ptsGenoa, Italy: 46% of 113 consecutive rosacea clinic pts St. Louis, MO: 51% of 63 consecutive GI clinic pts with rosaceaSt. 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)St. Louis, MO: 66% of 176 consecutive GI clinic pts with rosacea (incl. CH4+ pts)



33 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 controlsGenoa, Italy: 3/60 age matched controls St. Louis, MO: 3/30 healthy controlsSt. Louis, MO: 3/30 healthy controls (Lactulose gets to colon faster causes FP)



34 Rifaximin for rosacea: 1 st study Parodi et al. Am J Gastroenterol 2008;6:759-764. N=113 pts seen in Rosacea ClinicN=113 pts seen in Rosacea Clinic 83 F, 31 M, age 5283 F, 31 M, age 52 52/113 (46%) LBT+52/113 (46%) LBT+ 24/113 H.p.+ (7 had SIBO)24/113 H.p.+ (7 had SIBO) 7 pts treated for H.p. 1 mo after SIBO Rx (clinical response occurred with SIBO Rx)7 pts treated for H.p. 1 mo after SIBO Rx (clinical response occurred with SIBO Rx) GI sx response analyzed GI sx response analyzed



35 Rifaximin for rosacea Parodi et al. Am J Gastroenterol 2008;6:759-764. N = 52 LBT+ (H2 excretion)N = 52 LBT+ (H2 excretion) Rifaximin 1200 mg/d/10d vs. PlaceboRifaximin 1200 mg/d/10d vs. Placebo Randomized, blinded only to ptsRandomized, blinded only to pts IGA scoringIGA scoring 2 dermatologists (Kappa = 0.97)2 dermatologists (Kappa = 0.97) Additional studiesAdditional studies Cross-over for placebo groupCross-over for placebo group Open label used for SIBO-negative ptsOpen label used for SIBO-negative pts Subtype rosacea evaluatedSubtype rosacea evaluated



36 Randomized study results Parodi et al. Am J Gastroenterol 2008;6:759-764. Rifaximin normalized LBT in 28/32Rifaximin normalized LBT in 28/32 71% cleared rosacea (GA score 0)71% cleared rosacea (GA score 0) 21% marked impr. (GA score 1)21% marked impr. (GA score 1) Placebo 2/20 worsened, rest unchg.Placebo 2/20 worsened, rest unchg. GI sx sig. decreased with rifaximinGI sx sig. decreased with rifaximin



37 Courtesy of V. Savarino: Paroldi et al. Clin Gastroenterol Hepatol 2008;6;759-6. Before & 1 mo after 1200 mg/d/10d rifaximin



38 Note periocular and cheek improvement Courtesy of V. Savarino: Paroldi et al. Clin Gastroenterol Hepatol 2008;6;759-64.



39 Additional study results Parodi et al. Am J Gastroenterol 2008;6:759-764. X-over: placebo group treated open-labelX-over: placebo group treated open-label 17/20 LBT normalized17/20 LBT normalized 15 of the 17 had rosacea cleared15 of the 17 had rosacea cleared 45/52 total eradication with rifaximin45/52 total eradication with rifaximin 35/45 cleared35/45 cleared Improvement maintained in 96% at 9 moImprovement maintained in 96% at 9 mo 2 w pap/pust returned & Re-Rx worked2 w pap/pust returned & Re-Rx worked LBT- group treated (see next)LBT- group treated (see next)



40 Parodi et al. Am J Gastroenterol 2008;6:759-764. Rifaximin 1200 mg/d/10d (N=32) (N=20)



41 Rifaximin for subtypes Parodi et al. Am J Gastroenterol 2008;6:759-764. Flush (2)222 Fl/Erythosis (27)0-- Papules (8)654 Fl/Pap (34)1199 Fl/Ery/Pap (8)763 Pap/Pustules (7)444 Fl/Pap/Pust (16)13118 All four types (11)985 Patient type (N)SIBO positive Eradicated (LBT better) Rosacea cleared Pap/Pust groups had SIBO > non P/P (p non P/P (p<0.001)



42 Parodi study: critisms Baseline mean IGA not stated – delta not shownBaseline mean IGA not stated – delta not shown All sub-types includedAll sub-types included –Pust. +/- pap. was most impt to include (84/113 had one or both) Study not blinded to physiciansStudy not blinded to physicians –2 independent scores performed with high Kappa LBT used for SIBO DxLBT used for SIBO Dx –Potential for more false+ –Less invasive than jejunal aspiration



43 Second rifaximin study: methane Parodi. UEGS. Abstract 2008 Parodi. UEGS. Abstract 2008. 15 H2+ & 15 CH4+ rosacea pts15 H2+ & 15 CH4+ rosacea pts Rx #1: rifaximinRx #1: rifaximin H2 pts - most respondedH2 pts - most responded CH4 pts - little or no improvementCH4 pts - little or no improvement Rx #2: metronidazoleRx #2: metronidazole CH4 pts - majority with complete or significant clearanceCH4 pts - majority with complete or significant clearance (Note: need for dual therapy in IBS-methane pts) (Note: need for dual therapy in IBS-methane pts)



44 Rifaximin for rosacea: St. Louis Weinstock, Steinhoff. J Am Acad Dermatol 2013;68:875-6 Weinstock, Steinhoff. J Am Acad Dermatol 2013;68:875-6. N=63 pts (59 from screening colonoscopy)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)Dx by dermatolgist in 57; ETR in 50, PP in 9, refractory ocular in 4 (3 had E) Most did not have GI sxMost 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)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/10d28 LBT+ pts given rifaximin 1200 mg/d/10d Limitations: open-label, self-assessment by questionnaire and photos by ptsLimitations: open-label, self-assessment by questionnaire and photos by pts



45 Improvement: self-assessed Weinstock, Steinhoff. J Am Acad Dermatol 2013;68:875-6. 46% 25% 11% 18% Cleared Moderate Mild Unchanged Cleared Moderate Mild Unchanged or Marked or Marked



46 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



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



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



49 Subsequent patient experience Higher dose to match IBS studies and additional Rx for complex pts: Rifaximin 550 mg TID for 14 daysRifaximin 550 mg TID for 14 days Comprehensive post-SIBO Rx for complex patientsComprehensive post-SIBO Rx for complex patients



50 Before & 5 wk after rifaximin 1650/mg/d/14d Eyes, RLS fatigue, memory, and nail strength Improved. Case 2



51 Before & 1 mo after rifaximin 1200 mg/d/10d** **Pi-IBS and rosacea (worsened after colon cancer resection)



52 Before & 1 mo after rifaximin 1650 mg/d/14d 1.25 yrs after first treatment



53 Before & 1 mo after rifaximin 1650mg/d/14d (Failing Oracea, Metrogel, Protopic)



54 2 mo after end of rifaximin Less redness on cheek, nose, temple and beard area



55 Forehead papules: rifaximin 1650 mg/d/14d 1 mo later: reduction of papules



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



57 Facial rosacea study: 2014 Facial rosacea study: 2014 Prospective, R, DB, X-O studyProspective, R, DB, X-O study PPR pts at UCSFPPR pts at UCSF Rifaximin 1650 mg/d/14d vs. placebo (regardless of LBT test result – blinded)Rifaximin 1650 mg/d/14d vs. placebo (regardless of LBT test result – blinded) Rosacea-SIBO diet for all subjectsRosacea-SIBO diet for all subjects IGA scoring and masked photographs of face over 8 wksIGA scoring and masked photographs of face over 8 wks Steinhoff, Weinstock



58 Ocular surface disease (OSD) Dry eye Dry eye Aqueous deficiency Aqueous deficiency Meibomian gland dysfunction Meibomian gland dysfunction Lipid deficiency: ocular rosacea Lipid deficiency: ocular rosacea Eye lash loss Eye lash loss Tearing disorders Tearing disorders Corneal abrasions Corneal abrasions Facial rosacea & ocular rosacea Facial rosacea & ocular rosacea 4% – 58% concordance 4% – 58% concordance



59 Rifaximin 1650/mg/day/14d: Day 0 & Day 14 Less edema, redness and foreign body symptoms after Rx



60 Rifaximin 1650/mg/day/14d: Day 0 & Day 14 Less injection of conjunctiva, decreased lid margin inflm, no symptoms



61 2 wks after 2 wks rifaximin 1650/d/14d 2 wks after 2 wks rifaximin 1650/d/14d



62 Ocular rosacea study: 2014 Prospective study over 8 wksProspective study over 8 wks Rifaximin 1650 mg/d/14d for all subjects Blinded to LBT test resultRifaximin 1650 mg/d/14d for all subjects Blinded to LBT test result Rosacea-SIBO diet for all subjectsRosacea-SIBO diet for all subjects Standardized IGA ocular grading and photographs of eyes and faceStandardized IGA ocular grading and photographs of eyes and face Berdy, Weinstock, Steinhoff



63 Rosacea and other SIBO diseases/disorders



64 Scleroderma: case study Sclerodactyly, Raynaud’s, GERD, oral changesSclerodactyly, Raynaud’s, GERD, oral changes GI SIBO sxGI SIBO sx –Bloating –Fatigue –Fe & B12 def New SIBO sxNew SIBO sx –RLS 1 –Rosacea of face (not reported) (Oc. Ros. - 45 SSc pts: 49% dry eyes, 40% blepharitis 2 ) (Oc. Ros. - 45 SSc pts: 49% dry eyes, 40% blepharitis 2 ) 1). Sleep Med 2002;3:341-5. 2). 1). Sleep Med 2002;3:341-5. 2). Arch Clin Exp Ophthalmol 2012;250:1051-6.



65 Scleroderma pt 4 wks after 2 wks Xifaxan and metronidazole (failed doxycyline) Rosacea: nose and cheeks much better RLS: completely better



66 Diabetes Meibomian gland dysfunction study in a general populationMeibomian gland dysfunction study in a general population N=619 people with and without eye sxN=619 people with and without eye sx Asx MGD in 22%Asx MGD in 22% Diabetes OR = 2.2Diabetes 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.



67 Rheumatoid arthritis MGD study (cont.)MGD study (cont.) Sx MGD in 8.6% of populationSx MGD in 8.6% of population Facial rosacea pts: OR = 3.5Facial rosacea pts: OR = 3.5 Rheumatoid arthritis pts: OR = 16.5Rheumatoid 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.



68 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 - cleared60 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 - cleared46 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 next32 y.o. F – see next Weinstock. J Clin Gastroenterol 2011; Weinstock. J Clin Gastroenterol 2011; 45:295-297.



69 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.



70 Subsequent effect of 8 wks biologic therapy (adalimulab)



71 Celiac disease Celiac disease/SB diseaseCeliac disease/SB disease –20 of 60 rosacea pts had abnormal jejunal Bx –4/20 were typical for celiac disease Possibities: IL-8 and celiacIL-8 and celiac Primary effects of SIBO in jejunumPrimary effects of SIBO in jejunum Watson et al. Lancet 1965;7402:48-50.



72 Parkinson’s disease 70 PD pts, 22 controls70 PD pts, 22 controls –Sebumetry, corneometry, pH 51% hyperhidrosis (low pH)51% hyperhidrosis (low pH) 32% cold/hot flush*32% cold/hot flush* 19% rosacea*19% rosacea* 19% seborrhoea on forehead19% seborrhoea on forehead MOA: “possible loss of vasostability d/t autonomic dysregulation in skin”MOA: “possible loss of vasostability d/t autonomic dysregulation in skin” Fischer et al. J Neural Transm 2001;108:205-13.



73 Parkinson’s disease Alpha-synuclein damages enteric neurons and reduces GI motility (prior to CNS Sx) Prevalence of SIBO (LBT+) 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 – - 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.



74 Steatohepatitis and rosacea?



75 Steatohepatitis Liver expert poll: rosacea seen in NASH & ETOH, not viral or autoimmune hepatitis (Poordad, Bacon, Tetri)Liver expert poll: rosacea seen in NASH & ETOH, not viral or autoimmune hepatitis (Poordad, Bacon, Tetri) Steatohepatitis (w/ & w/o ETOH)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.



76 Obesity and inflammation CytokinesCytokines –Incr. T-cells, TNF-alpha, IL-6 DysbiosisDysbiosis –IBS & steatohepatitis link –Methane-obesity link Fat absorption linked to histamine release (in rats)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.



77 Alcohol abuse Alcohol – flushAlcohol – flush 1 ref for rosacea (not controlled)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.



78 Theoretical links in pathophysiogy Rosacea ? Upregulates local immune & inflm. ? Increases dermal vascular permeability ? Neurogenic inflam. or incr. in collagenase and bacterial virulence * ? Food triggers SIBO Systemic IL-8 (or IL-6/TNF, IL-18 in NASH) LPS, IL-8 and integrin B-7 Systemic substance P FODMAPs/bacterial activity Histamine foods and mast cells *Miljouin. PLoS One 2013



79 Summary Diseases and SIBO occurs after enteric infectionsDiseases and SIBO occurs after enteric infections SIBO causes systemic inflammationSIBO causes systemic inflammation Rifaximin helps “Rosacea-SIBO”Rifaximin helps “Rosacea-SIBO”



80 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



81 Activated OGFr Endothelial cell barrier maintained Lymphocytes production 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.



82 Activated OGFr SRC and pY production leads to endothelial cell barrier disruption (Integrin could worsen net effect) LPS & OGFr – role in rosacea?



83 DecreasedOGFrActivityShort-term Cells perceive perceive OGFr OGFr reduction reduction Potential Rx for LPS-induced inflam: Naltrexone binds to OGFr



84 Activated 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.



85 Role of Mast Cells in IBS Abdominal pain and severity correlated with the number of mast cells <5µm Barbara. Gastroenterology. 2004;126:3. NormalIBS Proximity to nerves Elevated tryptase and histamine



86 Rosacea food triggers Direct Hot temperature Hot temperature Histamine foods Histamine foods Indirect Indirect FODMAPs FODMAPs Spicy food Spicy food History History 1926 – Carbohydrate intolerance (Kendall) 1926 – Carbohydrate intolerance (Kendall) 1966 – GI sx but Nl mucosal enzyme activity 1966 – GI sx but Nl mucosal enzyme activity 2008-13 – SIBO link and risks of FODMAPs 2008-13 – SIBO link and risks of FODMAPs



87 Food triggers: GI perspective Spicy foodSpicy food Increase capsaicinIncrease capsaicin Hot drinksHot drinks Release vasoactive proteinsRelease vasoactive proteins Histamine foodsHistamine foods Activation of mast cellsActivation of mast cells FODMAP foodsFODMAP foods Increase fermentation & inflammationIncrease fermentation & inflammation Substance PSubstance P Hydrogen sulfideHydrogen sulfide



88 Spicy food (45%)Spicy food (45%) Hot drinks (36%)Hot drinks (36%) Histamine foodsHistamine foods –Red wine –Aged cheese –Yogurt –Beer –Bacon Other triggersOther triggers –Chocolate –Vanilla –Soy sauce –Yeast extract –Vinegar –Liver Wilkin J, National Rosacea Society Survey. Alcohol (52%)Alcohol (52%) Fruit (13%)Fruit (13%) –Citrus fruits –Red plums –Raisins & figs –Tomatoes –Bananas Dairy (8%)Dairy (8%) –Aged cheese –Yogurt VegetablesVegetables –Broad-leaf beans & pods –Avocado –Eggplant –Spinach



89 General principles of SIBO Rx Diagnosis Lactulose breath test Lactulose breath testvs.History Non-absorbed ABx Rifaximin Rifaximin Comprehensive Rx Improve motility Restore permeability Reduce inflammatio n Weinstock, Fern, Thyssen, Todorczuk. Am J Gastroenterol 2006;110:A1124



90 Repeat rifaximin Rx for IBS N in study N repeat Rx1 st responseRe-treatment responses 1691 – 675% 1)54/65; 2) 38/40; 3) 17/18 had 100% response 991 – 774% 49 pts re-Rx avg 2.2x over 3.8 yrs had 100% response; 9% needed intermittent rifaximin since prokinetic Rx failed 841 – 269% 1)16/16; 2) 4/4 had 100% response Pimentel. Dig Dis Sci 2011. Weinstock. Dig Dis Sci 2011. Yang, Dig Dis Sci 2008.



91 H. pylori controversy Local gastric infection with systemic immune changesLocal gastric infection with systemic immune changes Cag-A more virulent – prevalent in Poland & ChinaCag-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?



92 H. pylori: “plausible study” N=60, 31-72 y.o. Polish pts with P/P/E/F N=60, 31-72 y.o. Polish pts with P/P/E/F 60 age- & gender-matched NUD pts w/o rosacea 60 age- & gender-matched NUD pts w/o rosacea Hp prevalence in rosacea 88% vs. 65% in NUD 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 Rosacea pts: 67% were cytotoxin-associated gene A (CAG-A) positive vs. 32% of controls pts OCM Rx: 51/53 rosacea pts became Hp- 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 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%) Rx decreased IL-8 (65%) and TNF-alpha (72%) Szlachcic et al Szlachcic et al J Physiol Pharmacol. 1999;50:777-86.



93 Complex Regional Pain Syndrome Reflex Sympathetic Dystrophy or Reflex Neurovascular DystrophyReflex Sympathetic Dystrophy or Reflex Neurovascular Dystrophy Severe pain, swelling & changes in skin often in arm or legSevere pain, swelling & changes in skin often in arm or leg Spreads throughout the body in 92%Spreads throughout the body in 92% Neurogenic inflammation, nociceptive sensitisation vasomotor dysfunction & aberrant response to tissue injury 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.



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99 StageMGD GradeSymptomsCorneal Staining 1 + (minimally altered expressibility and secretion quality) None 2 ++ (mildly altered expressibility and secretion quality) Minimal to MildNone 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.



100 N = 60 rosacea pts & 50 controls (66% F)N = 60 rosacea pts & 50 controls (66% F) Waist, BMI, glucose, CRP, lipidsWaist, BMI, glucose, CRP, lipids Median duration of rosacea 36 moMedian 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. controlsHigh 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 CVDRosacea 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



101 Healthy GI microbiota Immune system developmentImmune system development Epithelial integrityEpithelial integrity Inhibition of NF-kB activationInhibition of NF-kB activation Anti-inflammatory metabolite productionAnti-inflammatory metabolite production Colonization resistanceColonization resistance Mucus homeostasisMucus homeostasis Bile acid deconjugationBile acid deconjugation Lipid metabolismLipid metabolism Insulin resistanceInsulin resistance



102 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 CNSStress 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

