How do we control inflammation? Leonard Weinstock, MD Specialists in Gastroenterology, LLC 11525 Olde Cabin Road, St. Louis, MO
How do we control
inflammation?
Leonard Weinstock, MD
Specialists in Gastroenterology, LLC
11525 Olde Cabin Road, St. Louis, MO
Disclosures
Speakers Bureaus
Salix
EnteraHealth
Forrest
Off label use of medications
Off Label Use of Meds
Common for GI
Proton pump inhibitors
Anti-depressants
Prednisone, Immune-suppressants
Antibiotics
New for GI
Low dose naltrexone
Legal and ethical in the confines of one’s own practice
Common Inflammatory Conditions
DISEASES
Crohn’s disease
Ulcerative colitis
CC & LC
SIBO
IBS
Celiac disease
SYNDROMES
RLS
Rosacea
Fibromyalgia
Pelvic pain disorders
CFS
Microbiome
10x # bacteria vs. # human cells
Balance = health
Dysbiosis = disease
TNF-α Interleukins PG LPS NO2 H2S
Substance P Antigens Antibodies Thy-1
Mast cells Lymphocytes Eosinophil Neutrophil
All of the above altered in dysbiosis, IBS, SIBO,
and extra-intestinal syndromes
Overview of Therapy
• Generally suppress/modulate inflammation
• Specifically alter functions & abilities of
certain WBC
• Alter microbiome and mucosal immunity
– Antibiotics, Probiotics, Dietary, IgG, FMT
• Improve innate regulation of immunity and
inflammation
– Endorphins
Drug-induced Infection &
Mortality in Crohn's
N = 6273; 3420 had infliximab; 2853 had other-Rx-only
Mean length of F-U = 5 yrs; Infliximab group had
moderate-to-severe (31% vs. 11%) or severe-to-fulminant (3%
vs. 1%) disease severity
Mortality increased with:
Prednisone, narcotic use, and age
Infections increased with: Moderate-to-severe disease activity, narcotic use,
prednisone, and infliximab
Prednisone
• MOA
– Suppress neutrophils activity
– Alter vascular permeability
– Decrease macrocyte Fx
– Altered arachidonic acids
– Suppress circadian IL-6
• Protection
– Vitamin D and Calcium
– Alternative steroids
• Budesonide
– Short acting
– Slow release for colon
• Local: suppository, enema,
foam
• Adverse Events – Mood swings
– Insomnia
– Edema
– Hypertension
– Hyperglycemia
– Weight gain
– Thin skin, bruising
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– Increased risk of infections
– Adrenal insufficiency
– Glaucoma, Cataracts
– Osteoporosis
5-ASA
• MOA
– Inhibit 5-lipoxygenase
(and thus leukotrienes)
– Free-radicle scavenger
(blocks bad effects of
neutrophils)
• Protection
– Check creatinine
– pH & distribution
– Alternative forms
• Local
– Suppository
– Enema
• Adverse Events – Diarrhea – 3%
– Hair loss
– Headache
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– Hypersensitivity reactions
• Fever
• Bone marrow diseases
• Pancreatitis
• Rash
• Renal failure
Thiopurines: Aza and 6-MP
• MOA
– Block lymphocyte
proliferation, activation,
and effector mechanisms
• Protection
– Check TPMT (issue with
11% population)
– Correct mg/kg dosing
– Vaccines
– Avoid infections
– Check CBC/LFT
– Check 6-TG levels
• Adverse Events – Nausea
-----------------------------------
– Allergic pancreatitis (3%)
– Leukopenia
– Anemia
– Hepatotoxicity (6-MMP)
– Increased risk of infections
– Increased risk of lymphoma (esp. H-S lymphoma in combo with anti-TNF Rx)
– Skin cancer
Thiopurines: Observed Cancers
Only skin cancer and lymphoma are higher than controls
Methotrexate • MOA
– Inhibits folate dependent enzymes
– Accumulates adenosine resulting in lymphotoxic, immunosuppressive, & anti-inflammatory autocoid
– Decreases pro-inflammatory IL, leucotriene B4, and antibodies
– Increases anti-inflam. IL
– Impairs neutrophil chemotaxis
• Protection – Give folic acid
– Avoid with renal disease and sulfa Rx
– Vaccines
– Avoid infections
– Check CBC/LFT
– ? Liver Bx
• Adverse Events – Nausea
– Rash
– Diarrhea
– Stomatitis
--------------------------------
– Bone marrow suppression
– Liver toxicity
– Pneumonitis
– Teratogenicity
– Spontaneous abortions
Hydroxychloroquine: Plaquenil
• MOA
– Migrates into
inflammatory cells –
reduces chemotaxis,
phagocytosis and
superoxide production by
neutrophils
– Reduces Toll like activity
• Protection
– Base line and periodic
ophthalmologic
examinations (including
visual acuity, expert slit-
lamp funduscopic, and
visual field tests) should be
performed every 6 mo
– Periodic blood tests
• Adverse Events
• Headache
• Dizziness
• Diarrhea, anorexia, nausea, abdominal cramps
• Changes in visual acuity, visual field, or retinal macular areas (pigmentary changes, loss of foveal reflex)
Anti-TNF-α therapy: Infliximab, Adalimulab, Certiluzimab
• MOA – Neutralizes TNF-α
released by T-cells
– Splits lymphocytes via complement fixation or cytoxicity
• Protection – Vaccination:
• dead viruses
• Wait 2 mo after live viruses
– Exclude Tb and histoplasmosis
• Adverse Events – Infusion reactions
– Injection pain
– Increased risk of infections
– Antibodies • Lupus
• Arthritis
• Antibodies against the drug
– Loss of efficacy
– Delayed hypersensitivity with rash, muscle aches, arthritis
– Lymphoma
Anti-Integrin therapy: Vedolizumab
• MOA
• Protection
– Observe
• Adverse Events
– Potential increased risk of infection
– Rare malignancy – similar to placebo
Antibiotics: Metronidazole
• MOA
– Anaerobic anti-biotic coverage
– Possible direct anti-inflammatory effect
• Protection
– Short-term use if possible
– Education about neuropathy
• Adverse Events
– Metallic taste
– Neuropathy
Antibiotics: Ciprofloxacin
• MOA
– Broad spectrum antibiotic coverage
• Protection
– Short term use if possible
– S. boulardii (?)
• Adverse Events
– C. difficile
– Rash
– Tendon rupture
Antibiotics: Rifaximin
• MOA
– Broad spectum, gut
directed antibiotic –
anaerobic and aerobic
coverage
• Adverse Events
– Equivalent to placebo
– Extremely rare rash or
candida owing to poor
systemic absorption
Antibiotics: Herbal
• MOA
– Garlic – inhibits NF-Kappa B
– Inhibit thiol enzymes
– Inhibit CYP2E1 activity
• Examples – Neem
– Goldseal
– Oregeno
– Berberine
– Allicin (from garlic - allium)
– Candibacine
• Adverse Events
– Nausea
– Berberine – reduce glucose
– Drug interactions for allium owing to CYP2E1 and CYP3A4 activity
Herbal Rx in IBD 21 randomised controlled trials (14 UC; 7 CD) w 1484 pts
UC
• Aloe vera gel, Triticum aestivum (wheat grass juice),
Andrographis paniculata extract (HMPL-004) and
topical Xilei-san were superior to plcb in inducing
remission or response
• Curcumin: superior to plcb in maintaining remission
• Boswellia serrata and Plantago ovata were as effective as
mesalazine
• Evening primrose oil similar relapse rates as omega-3
fatty acids in the Rx UC
CD
• Wormwood and Tripterygium wilfordii were superior to
plcb in inducing remission, and preventing clinical
recurrence of post-operative CD
Probiotics
• MOA – Improve immunity
• Utility
– Ulcerative colitis
– Bloating
– Diarrhea
– Constipation
– Irritable bowel syndrome
– ?Crohn’s disease
• Adverse Events
– Bloating
– Constipation
– Diarrhea
– Expense
– Infection of central lines
– Sepsis in
immuno-compromized patients
Anti-Inflammatory Diet
Specific aspects
• Omega-3 fatty acids
• Ginger, curry (turmeric), cumin
• Tea (white, green, or oolong)
• Red wine - antioxidant activity
General diet
• Fats
• Carbohydrates
• Protein
• Fiber
Anti-Inflammatory Diets
Specific examples
– Specific carbohydrate diet (SCD)
– Gluten free diet (GFD)
– GAPS (Gut and Psychology Syndrome) diet
– Dr. Weil’s diet
Omega-3 & -6 fatty acids
Omega-3 - anti-inflammatory effects • Oily fish (salmon, sardines, herring, and
black cod)
• Walnuts
• Flaxseeds
• Hemp seeds
• Kelp or fish oil supplements
Omega-6 – pro-inflammatory
• via cytokine production
• Oil-rich seeds - oil extracted from seeds
used in snack & fast foods
Ginger, Turmeric, Cumin
Ginger
Suppresses prostaglandin synthesis through
inhibition of cyclooxygenase-1 and - 2
Turmeric
Includes two dozen anti-inflammatory
compounds, including six different COX-2-
inhibitors
Cumin
Activates NFκB in macrophage cells and
pro-inflammatory cytokines
Red Wine
• Red wine polyphenol increased the number of
Enterococcus, Prevotella, Bacteroides,
Bifidobacterium, Bacteroides uniformis,
Eggerthella lenta, and Blautia coccoides-
Eubacterium rectale groups (P < 0.05)
• In parallel, systolic and diastolic blood pressures
and triglyceride, total cholesterol, HDL cholesterol,
and C-reactive protein concentrations decreased
significantly (P < 0.05)
• Cholesterol and CRP benefits were linked to
changes in the bifidobacteria number
Am J Clin Nutr. 2012
Fats
Good • Unsaturated fats
• Olive oil, nuts, oatmeal, avocado, sesame oil and seeds, and soybeans
Bad
• Saturated fats
• butter, cream, high-fat cheese, fried chicken and fatty meat, and palm kernel oil
• Trans fats
• margarine, vegetable shortening, partially hydrogenated oils
Carbohydrates
Good
• Phytochemicals and antioxidants digest
slowly, reduce blood sugar spikes which
promote inflammation
• Whole grains, beans, sweet potatoes,
squash, berries, cherries, apples, and pears
Bad
• Advanced glycation end products (AGEs)
• High fructose corn syrup, bread, white
potatoes, crackers, chips, pastries,
sweetened drinks, refined/processed/fast
foods
AGEs
• Formed outside and inside the body
• Makes cells stiffer, less pliable and more
subject to damage and premature aging
• Formed by BBQ, frying, roasting, boiling
• Barbecued foods are high in AGEs
• Cigarette smoking increases AGEs - formed
when tobacco leaves are dried
• Certain foods promote glycation in the body –
especially fructose and galactose
Protein Good
• Eat more vegetable protein (soy foods, beans,
lentils and other legumes), whole grains, seeds,
nuts, and oily fish
• Soy foods contain isoflavones which have
antioxidant activity and have been suggested to
lower CRP/inflammation levels
Bad
• Eat less meat and poultry, which contain pro-
inflammatory fats
Fiber
• Soluble vs. insoluble – Soluble turns to gel and reduces cholesterol
– Insoluble fiber adds bulk to the stool
• Insoluble: fruit (esp. berries), vegetables (esp. beans), wheat bran, and whole grains
• Soluble: oat bran, barley, nuts, seeds, beans, lentils, peas, and some fruits and vegetables
• 30-40 grams of fiber each day - tolerance varies
• Fiber cereals is best single source per serving
Supplements
Daily MVI-mineral includes key antioxidants
–Co-enzyme Q10 - 60 to 100 mg/d with
largest meal
–Vitamins B9, C, E, and D
–Selenium
Dr. Weil's Anti-Inflammatory Diet
http://www.drweil.com/drw/ecs/pyramid/press-foodpyramid.html
Immunoglobulins: SBI
• Bovine serum immunoglobulins – EnteraGam
• Purified from bovine blood
• 25 yr use in pig farming – early weaned piglets
have reduced immunity, increased infections
and poor growth
• Introduced in 2013 for treatment of enteropathy
in man
Immunoglobulins: SBI
SBI and IBS
Single-center retrospective study
IBS D/M pts
N = 11 LBT + who failed rifaximin
and 13 LBT – who failed other therapy
SBI and IBS
Naltrexone
Anti-opioid (anti-narcotic)
FDA-approved in 1985 for addictions
Normal dose: 100 mg
LDN: History
1979 - 2015: Penn State endorphin research
1985: Rx for AIDS (NYC)
Mid 90’s: Rx for MS (NYC)
Zagon et al. Science 1983;221:671-3.
Bihari. AIDS Patient Care. 1995;9:3.
LDN: Rx Reports
Published
Cancer
AIDS
Fibromyalgia
MS
Complex regional pain syndrome
IBS
Crohn’s Disease
Ulcerative colitis
Anecdotal
CFS
RA, AS, SLE
Parkinson's disease
Hailey-Hailey & Psoriasis
Rosacea & Eczema
RLS
IC & CP
Sarcoidosis
Dercum’s disease
1100 SIG patients
Endogenous Opioids
B-endorphins, enkephalins, endomorphin, dynorphin
Opioid cells locations:
Entire nervous system
Adrenal glands
GI tract
Myenteric plexus
Mucosal plexus
Intestinal endocrine cells
Endorphins: Functions
Regulate cell growth
Decrease inflammation
Decrease permeability
Stabilize Toll-like receptors
Decrease microglia activation
Decrease cytokine release
Shift from TH2 to TH1
Improve GI motility
Activated
Cell
Regulates
T- & B-cell
production
Maintains
blood vessel
barriers
Opioid Cell/Receptor Functions
Endorphins
How Does LDN Work?
LDN displaces endorphins from
receptors for 4 hours
Cells sense opioid deficiency and rebound
via a positive feedback mechanism
Receptors increased
Met-enkephalin production x 12-15 fold
Activated
Receptors
Endorphins &
receptors lead
to decreased
T- and B-cell
activity & less
permeability
LDN effect
Ulcerative Colitis: LDN Rx
Weinstock. J Clin Gastroenterol 2014;48:742.
Pt failing Remicade – high risk of colectomy
Now in remission 6 years – LDN added to biologic Rx
Crohn’s Disease: LDN Rx 40 y.o. WF s/p total colectomy; intestinal recurrence
4 yrs later; failing Remicade: diarrhea and fatigue
LDN 4.5 mg added; Endo & Clin remission in 2 mo
Remission 5 years
CD and MS: LDN Rx
CRC screening of severe MS pt – ileitis without sx
2 weeks: MS clinical benefit
1 year: MS clinical benefit; ileal ulcers healed
RLS – a complex disease
38 highly-associated disorders
Systemic inflam/immune disorders - 95%
Systemic iron def. - 43%
Peripheral neuropathy - 40%
SIBO - 32% (only 14 tested for SIBO – all positive)
RLS brains are opioid deficient and this alters dopamine/iron interaction
Weinstock, Walters. Sleep Med Rev 2012;16:341-54.
Walters et al. J Neurol Sci 2009;279-62-5.
RLS: LDN Rx
Current chart review N=74
Complex Regional Pain Syndrome
CRPS = Reflex Sympathetic Dystrophy
Severe pain, swelling & skin changes
Pathophysiology
Neurogenic inflammation
Glial pain sensitization
Vasomotor dysfunction
Attacks triggered by inflammation 4 roles for
LDN
CRPS: SIBO and LDN Rx
53 y.o. WF 12 yr pain, 40 yr IBS, yrs poor
sleep, & Sx for 45 yrs of Ehlers-Danlos
Abnl LBT and sleep study:
Xifaxan & LDN
CPAP
Relapse at 1 yr:
Xifaxan
CPAP Rx maximized
Promotility Rx
LDN continued
Remission 1 mo later
Remission & successful retreatment
Weinstock et al. Pain Physician. Submitted 2015
LDN Adverse Events
10% in CD studies
40% in GI disorder study
67% return of AE surveys
Included many IBS pts
Minimize AE
Start with 1 mg
AM dosing decreases insomnia
Regulate Immunity and
Reduce Inflammation:
Primum non nocere
"first, do no harm"