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

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– 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

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– 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"