Management of Autoimmune &

Autoinflammatory Disease:
Case Studies
Dampening the Fire.
Robert Rountree, M.D.
Advanced Practice Module:
The Many
y Faces of Immune Dysregulation
y
g
and
Chronic Inflammation
Santa Monica, CA
October 2010

Obj ti
Objectives
Explain the role that genetic
susceptibility
tibilit does,
d
and
d does
d
not,
t play
l
in the development of autoimmunity
Analyze case-based treatment
protocols for the management of
autoimmune diseases
Understand the roles that innate
i
immunity,
it tolerance
t l
to
t microbes,
i
b
and
d
environmental triggers including diet &
toxins play in the management of
autoimmune diseases
diseases.

Horror Autotoxicus
I
Immune
reactivity against self
lf
Term coined by Paul Ehrlich (German bacteriologist)
Father of modern science of immunology
Winner of Nobel Prize in medicine (1908)

Ehrlich believed autoimmunity incompatible with life:

Immune response could ONLY be towards foreign antigens
Self-reactive lymphocytes are silenced or tolerized

Paradigm
g long
g unchallenged
g despite
p counter
evidence (e.g., lupus autoantibodies; AI hemolytic
anemia)
Autoimmunity
y eventually
y acknowledged
g in 1940-50s
as cause of many chronic diseases

Autoimmune Disease:
Broad Definition
Self-directed tissue inflammation, resulting from
loss of tolerance by aberrant dendritic cell, B & T
cell responses with development of
immune reactivity towards native antigens
Adaptive
p
immune response
p
((antibodies, activated
T lymphocytes) appears to play predominant role
in clinical disease, although innate immunity may
be the ultimate driver
Pathophysiology
P th h i l
is
i ongoing
i & multifactorial:
ltif t i l
organ or tissue-specific antibodies may predate
clinical disease by many years
PLoS Med, 2006, Vol 3(8): 1242-1248

Weaknesses of Autoimmune Disease =

Self vs Strangers
Strangers Concept
Self / nonself discrimination appears
lacking for cancers
Most individuals harbor autoreactive
l
lymphocytes
h
t without
ith t any sign
i off
autoimmune disease
Lack of autoantibodies or MHC
associations found for many A.D.s
PLoS Med, 2006, Vol 3(8): 1242-1248

Danger Signal Theory

(P ll M
(Polly
Matzinger)
t ing r)
Immune system is less concerned with
di ti
distinguishing
i hi
self
lf from
f
non-self
lf
(strangers) than it is with
mounting responses to danger:
entities that do damage
Risk of harm is determined by antigen
presenting cells (via induction of
costimulatory molecules by alarm signals)
Stranger + danger inflammation
Science, 2002, Vol 296: 301-305

Innate Immune Mechanisms That Contribute to Autoimmune Disorders

N Engl J Med 2007;Vol 356:1263-1266

At least 20% of the population has

genes that predispose them to
autoimmune development.
development But
only a fraction of them go on to
d l p full
develop
full-blown
bl n autoimmune
ut immun
disorders. Other mitigating factors
( i
(triggers
& mediators)
di
) must b
be
involved

Mild forms of the autoimmune response probably

occur naturally in most people. But, for people with a
predisposition
di
iti tto autoimmunity,
t i
it environmental
i
t l
factors, such as toxic chemicals, drugs, bacteria or
viruses, may trigger a full-fledged response.
Press release: September, 1999
National Institute of Environmental Health Sciences,
NIH
www.nih.gov/news/pr/sept99/niehs-28.htm

Autoimmune Disease: Delayed

Gratification
M
Many autoimmune
t i
diseases
di
do
d nott develop
d
l
spontaneously, but instead evolve through an
extended germination period before they become
clinically evident
evident
Well over 10 million people test positive for ANA,
years before they have any symptoms.
This implies the presence of additional
environmental factors that dampen or amplify the
process over time.

Case #1
Recurrent episodes of severe abdominal pain &
swelling; vomiting and diarrhea
35 year old female of Armenian descent
14 yr. Hx of above Sx, recently in frequency,
grade fever;; acute,, mildly
y WBC.
Assoc. with low g
Episodes consistently triggered by emotional stress.
Peritoneal tap during one of the episodes revealed
an abundance of neutrophils,
p
, but was sterile.
Episodes had d after Rx with daily colchicine
+ low dose amitriptyline (25 mg/d).
y p
helped
p with ondansetron &/or
Symptoms
dicyclomine

Case #1
Recurrent episodes of severe abdominal pain &
swelling; vomiting and diarrhea
Review of systems:
chronic diarrhea
diarrhea, constant churning
churning, gurgling
gurgling
recurrent severe migraines, recurrent joint aches (esp. fingers),
insomnia, chronic fatigue, dysthymia
allergic rhinitis
Laboratory
L b
t
findings:
fi di
ANA + 1:160; anti-ds DNA negative
Anti-CCP, rheumatoid factor both negative
low DHEA
DHEA, pregnenolone
nl SPEP, quantitative IgG, A, D
nl CRP, ESR
nl C3, C4, C5, CH50
nl C1-esterase inhibitor function
Negative urinary porphyria screen

Case #1
Recurrent episodes of severe abdominal pain &
swelling; vomiting and diarrhea
Working diagnosis =
Familial Mediterranean Fever
aka
k relapsing
l
i
polyserositis
l
iti
However,
genetic testing
g
g (UCLA
(
FMF Clinic)) was negative
g
Alternative diagnoses?
recurrent angioedema
acquired C1 esterase deficiency?
nonspecific connective tissue disorder?

Patient with recurrent abd. pain, migraines

Single Nucleotide Polymorphisms

Case #1
Recurrent episodes of severe abdominal pain &
swelling; vomiting and diarrhea
Initial interventions:

Rice protein powder with anti

anti-inflammatory
inflammatory botanicals & FOS
Purified whey powder, high in immunoglobulins
Mixed flavonoid complex
DHEA; Licorice root; Pantothenic acid (high dose)
Fish oil capsules (EPA)
Probiotic (Lactobacillus GG)

Response: diarrhea stopped almost immediately; episodes in

frequency and severity, energy , Its amazing.
Follow-up (@ 4 years):
on similar therapeutic regimen, including 75-100 mg DHEA
still has episodic abdominal pain & migraines but severity & frequency much
reduced;; notes that salt and fat alleviate symptoms
y p
stress is most consistent trigger

Case #1
T Year
Ten
Y Follow-up
F ll
Much better overall. No major attacks of abd pain in several
years, occl mild flares with marked fatigue, diffuse muscle/joint
aches (flu
(flu-like),
like) headaches,
headaches & mild nausea -- lasting 1-3
1 3 days;
triggered by stress
Meds & supplements

Colchicine, 0.6 mg tid

D l
Duloxetine:
ti
40 mg: d
definitely
fi it l h
helps
l stabilize
t bili mood,
d d
decreases anxiety
i t
Licorice root +/- Cortef, 5-10 mg prn in am: definitely helps energy
DHEA, 75 mg + pregnenolone 30 mg: helps overall symptoms
Coenzyme Q10: 50 mg
Fish oil: 3 grams qd
Vitamin D3: 5000 IU
Probiotic: 100 CFUs qd
L-glutamine: 5 grams qd
Oral bovine immunoglobulin concentrate: 5 grams
Lumbricus extract (with Atractyloides, Poria, Grass-Leaf Sweetflag root),
3 caps bid: definitely helps with GI symptoms)

Familial Mediterranean Fever

One of several hereditary
yp
periodic fever syndromes
y
Multisystem autosomal recessive disorder of inappropriate
inflammation, with recurrent painful attacks of abdomen,
chest or joints
Sx = episodic (6-96 hrs.) fever with severe abdominal pain
(sterile peritonitis) +/- pleuritis, +/- monoarthritis +/erysipelas-like lesions of skin.
Amyloidosis is main complication (proteinuria).
Lab = inflammatory mediators (serum amyloid A,
fibrinogen, CRP), but only during attacks.
Rx = colchicine; prevents attacks in 60% of patients.
Drenth, J.P.H & J. W. Van der Meer, NEJM, 2001, Vol
345(24): 1748-1757

Familial Mediterranean Fever

Pathophysiology: neutrophil mediated
polyserositis
Defect in MEFV gene results in defective
pyrin, a protein found in serosal
neutrophils
t
hil that
th t deactivates
d
ti t chemotactic
h
t ti
factors elicited by inflammatory stimuli
Can overlap or co-exist with autoimmune
diseases (Hashimotos, Polyarteritis
nodosa)

Autoinflammation
Self-directed inflammation,, whereby
y
local factors (e.g., upregulated
cytokine signaling pathways) result
in activation of innate immune cells
(DCs, macrophages, neutrophils),
causing target tissue damage
This is independent of adaptive
immune responses
PLoS Med, 2006, Vol 3(8): 1242-1248

PLoS Med, 2006,Vol 3(8): 12421242-1248

Case #2
D mouth
Dry
th & constipation
ti ti
39 yo WF, well until premature birth of (healthy)
daughter 5 years prior
2 weeks postpartum: persistent severe dry
mouth; helped (slightly) by continuous gum
chewing
Rheumatologist: Sjgren's antibody panel all
negative, but probably has it
2nd child 2 years prior: 6 mos postpartum:
diffuse joint aches, mild morning stiffness (no
hot, red or swollen joints); then eyes feel
chronically irritated, like sand, also c/o marked
d li in
decline
i libido
libid
Hx: adopted; was conceived & grew up near Lake
Erie: very toxic area

Case #2
Dry mouth & constipation
Eval by D.C.: elevated lactulose/mannitol
excretion, low urinary testosterone, elevated
cortisol
Rxd fish oil, testosterone/progesterone cream:
little effect but sx gradually improved over 2
years
Current ROS:

mouth slightly better but still dry

eyes much better
joint pains almost gone
severe, chronic constipation; recent episode of diverticulitis
(taking antibiotics)
Low libido, "very moody with anxiety & panic attacks, I
dontt trust my body anymore
don
anymore

Diet: mostly Paleo, organic, some grains, little

junk

Case #2
Ph i l E
Physical
Exam
PE: sclera/conjunctiva
PE
l
/
j
ti moist,
i t nott inflamed
i fl
d
Neck: with parotid enlargement
Abd: p
palpable
p
stool in LUQ/LLQ
Q
Q
MS: all joints FROM without tenderness;
none boggy or hot
Neuro: reflexes symmetrical but sluggish
Skin: no rashes

Case #2
L b
Labs
CBC: WNL;; Chem-screen: WNL
CRP: 3.0mg/L
ANA screen: 0.47 units; Neg anti-CCP
N Sj
Neg
Sjgren's
' autoantibodies
t
tib di
(SS-A/Ro, SS-B/La)
SPEP: normal distribution
Food sensitivity panel (mediator release
test): multiple + foods (salmon & broccoli)

Case #2
Rx

Bowel rest with functional food powder

EPA + DHA:
DHA 780 mg tid
GLA: 240 mg tid
Berberine: 200 tid
L-glutamine: 5-10 grams
Magnesium citrate: 200 mg tid
Psyllium husks, flax meal
Probiotics
St Johns Wort; Passionflower
g, testosterone cream: 2.5 mg
g
DHEA: 25 mg,
Oligoantigenic diet (based on labs)

Case #2
9 month
h follow-up
f ll
Feeling much better: mouth not as dry-decreased need for gum; eyes OK, joints
OK (dancing regularly), libido improved on
hormones; mood better after starting
paroxetine
Repeat DHEA-S: 21.2 mcg/dL
Serum testosterone: 35 ng/dL (8-60)
Free testosterone: 0.5 ng/dL (0.3-1.9)
E2: 71.29 pg/mL

Sjgr n' SSyndrome

Sjgren's
ndr m
One of most common ADs (after RA)
3 million affected in US; 90% women;
typical onset age 40 & older
Immune system attacks secretory glands
& tissues
Biopsy is definitive -- antibody test
negative in 40% of cases
Assoc with 44% increased risk of
lymphoma

Sjgren's Syndrome:
Diverse Signs & Symptoms

Dry, irritated eyes (keratoconjunctivitis sicca)

Dry mouth, dysgeusia, dysphagia, thrush
Periodontal disease & early loss of teeth
Enlarged parotids
Dry cough
cough, recurrent sinusitis
sinusitis, lung infections
Vaginal dryness
Dry skin & rashes
Nonspecific GI Sx
Celiac disease / gluten sensitivity
Thyroiditis
M
Memory
loss
l
Paresthesias in hands & feet

The Influence of Sex Steroids on

Sjgren'ss Syndrome
Sjgren
We believe that the driving factor behind Sjgren's
syndrome
d
could
ld be
b lack
l k off androgens.
d
It has
h been
b
shown
h
that patients with Sjgren's syndrome have low
concentrations of circulating dehydroepiandrosterone
sulfate (DHEA-S)
(DHEA S) compared to age
age-matched
matched healthy
controls.
Our hypothesis is that patients with Sjgren's syndrome
suffer from an insufficient local androgen
g effect in the
exocrine target tissues of the disease because of low
systemic levels and/or ineffective local intracrine handling
of DHEA-S prohormone
Ann N Y Acad Sci. 2007 Jun;1108:426-32.

Case #3:
Rheumatoid Arthritis
36 year old white female
HPI: healthy until 2 yrs prior, onset of stiffness &
swelling in hands/feet; found to have + RA titer, Rxd
with NSAIDs, partial relief but Sx progressed to
elbows/knees; had to curtail sports; worried about
side
id effects
ff t off drugs
d
Initial Rx: elemental diet fast (rice protein powder) for
3 days, followed by modified elimination diet
Started
St t d GLA,
GLA 900 mg qd,
d fl
flax oil,
il antioxidants,
ti id t
glucosamine, 1500 mg qd, MCHA, bromelain
(enzyme formula), ginger/curcumin/bioflavonoids
After fast stated: Best
Best IIve
ve felt in two years.
years

Case #3:
36 yo with
i h RA
Lab: multiple +IgG foods; Rxd oligoantigenic
diet; low animal fat, deep sea fish,
nightshades
1 month later: slightly better
better. Added EPA
EPA,
1500 mg; GLA to 1200 mg
2 month follow-up: 50% better, jogging &
walking again; Rxd minocycline and
probiotics
4 month follow-up: almost normal
normal, had
improved within 4 days of starting antibiotic

Case #3:
36 yo with
i h RA
7 month follow-up: 100% better; only
remaining symptom was pain in one finger
finger,
otherwise at full activity level; had tried stopping
either minocycline or supplements but
symptoms
y p
recurred.
1 year later, retested IgG-food complexes and
modified diet accordingly, otherwise same
program.
Follow-up two years after initial visit. Did well,
then stopped minocycline for several months.
Had one flare and restarted, better within two
weeks Decided to stay on it along with
weeks.
supplements permanently.

Symmetric Synovitis in Early Rheumatoid Arthritis

Swan Neck Deformity

Conventional Management of Rheumatoid Arthritis

Initial Evaluation of the Patient with Polyarthritis

Case #4
Ch i d
Chronic
dermatitis
i i & arthralgias
h l i

HPI: 55 yo Hispanic woman in stable health until June, 1998, when she
experienced the acute onset of an intensely itchy
itchy, scaly
scaly, erythematous
rash, starting on her hands then spreading to her neck, elbows and
buttocks. She felt that the rash had started after a period of eating a
particularly liberal diet compared to her usual restrictions (based on
nutrition principles)
principles).
Consulted with a dermatologist, who prescribed a course of oral
prednisone. Helped initially, but after tapering, symptoms recurred even
worse than before, with spreading to include larger area of arms, both
popliteal areas
areas, and both postero-lateral
postero lateral thighs
thighs. A biopsy was then
performed which was read as "very suggestive of dermatitis
herpetiformis.
Started on gluten-free diet plus numerous supplements (GLA, zinc, Lglutamine) with mild improvement of rash prior to first visit

Case #4
Ch i d
Chronic
dermatitis
i i & arthralgias
h l i
PMH: No prior history of rashes but occasional problems with
dry and itchy skin (never severe).
severe)
Hx of allergic rhinitis that improved after several years of
immunotherapy. Long suspicious of food allergies, but could
never confirm any specific correlations.
Chronic,
Ch i recurrentt iintense
t
rectal
t l it
itching
hi for
f the
th pastt 12-13
12 13 years.
No Hx of recurrent diarrhea, gas or bloating.
Several year Hx of recurrent joint pain, primarily in the DIP's of
both hands. Joints would swell at times, but were never hot or
red.
d A
Approximately
i t l tten years prior
i bl
blood
d ttests
t ffor ""arthritis,"
th iti " were
reportedly negative.
Also c/o recurrent neck pain, chronic right-sided sciatica and
muscle aches regularly treated with chiropractic manipulation for
many years. MRI of the low back was reportedly normal.

Case #4
Ch i d
Chronic
dermatitis
i i & arthralgias
h l i

PMH: Diagnosed with osteoporosis in 1994, soon after the onset of menopause.
((Opposed
pp
to HRT & and instead took etidronate on a cyclic
y
basis for several
years.)

In 1990, observed that arthritic symptoms & rectal itching appeared to worsen
after ingestion of refined carbohydrates, alcohol, self-Dxd with candida
overgrowth & started yeast
yeast-free
free, sugar free diet
diet. Helped somewhat
somewhat, but
persistent symptoms led to adding a combination of ketoconazole &
triamcinolone cream, which controlled her symptoms to a tolerable degree.

Stressors: Time period between 1987 and 1990 was extremely stressful: mother
died of cancer; got divorced after many years of marriage; was involved in two
MVA's, both of which caused whiplash type injuries. She was (and continues to
be) an Associate Dean at a major University a job which she enjoyed, but
typically required 11 hour work days and little time off.

Case #4
Chronic dermatitis & arthralgias
Initial Labs
Intestinal p
permeability:
y Lactulose normal recovery
y at 0.3%,
mannitol depressed at 2%: elevated L/M ratio of 0.134
Celiac panel: Endomysial antibodies: normal (<5);
Anti-gliadin antibodies: normal (<4);
Anti-reticulin
Anti
reticulin antibodies: normal (<10)
CRP: <0.3; ESR: 4 mm/hr ANA: negative;
Rheumatoid Factor: positive at 43 IU/ml (normal 0-20)
WBC: 5000 with elevated eosinophils to 7.8% (normal up to
4 9%) otherwise
4.9%),
th
i nll diff
differential
ti l
Serum protein electrophoresis: unremarkable pattern
Total serum IgE: normal at 40 IU/ml
IgE-RAST
RAST negative for egg
egg, milk
milk, wheat,
wheat rye
rye, barley
barley, oat
oat, etc
etc.
IgE
DHEA-Sulfate: low at 60 mg/dl
Free T4: 1.14; TSH 2.04

Case #4
Chronic dermatitis & arthralgias
g
Clinical Course

Initial PE: confluent, marked erythema of both cubital fossae, both

axillae and both popliteal fossae with numerous raised papules
axillae,
papules, many
of which were excoriated and scaly.
No hot, swollen or deformed joints
Rx: Strict gluten-free diet, expanded to avoid corn, soy, dairy, yeast
GLA: 900 mg daily
EPA-DHA: 1500 mg
Quercitin: 1 gm tid
Ginger extract: 2 caps daily
L-glutamine
L glutamine to 10 grams qd
Multivitamin/mineral
Flax seed: 1/4 cup (ground)
Lactobacillus rhamnosus GG: 2 caps qd
Bovine colostrum: 6 caps daily
DHEA: 25 mg
Squalane oil (shark liver source): topical

Case #4
Chronic dermatitis & arthralgias
Clinical Course
Over the next 2 mos rash persisted with intermittent
exacerbations that client believed unrelated to diet. Continued to
have pain in fingers, along with intermittent erythema, warmth
and swelling in DIP's, especially the fourth digits. (not seen in
office )
office.)
Consulted with a dermatologist at the Univ. of CO. Repeat
biopsy confirmed DH. Told that "only 20% of patients with DH
improve on a gluten-free diet," was at high risk of developing
lymphoma and only choice was to take dapsone,
lymphoma,
dapsone otherwise sx
likely to be chronic. Client concerned about the potentially lethal
side effects of the drug -- determined to find a nonpharmacologic solution.

Case #4
Chronic dermatitis & arthralgias
Clinical Course

By April
April, 1999
1999, noted that her skin was getting increasingly more
manageable. Became aware that certain foods, especially soy
products, could produce a reaction within two hours of ingestion. The
more strict she was with her diet, the more the inflammation would
cool off in skin.
Continued aching in DIP's, which was not impacted by the dietary
changes. No morning stiffness, but the pain & swelling became more
chronic. Quercitin & ginger extracts seemed to alleviate the pain but
never eliminated it completely. The physical changes were subtle at
first but eventually she did develop mild palpable hypertrophy of the
first,
DIP's, primarily of the 4th digits.
By July, 1999, her skin "almost normal," however, became aware that
exposure to chemicals, such as perfume, would make her feel itchy all
over,, especially
p
y face.

Case #4
Chronic
C
o c dermatitis
de at t s & aarthralgias
t a g as
12 year follow-up (2010)
Subjective:
S bj ti
I ffeell great
t (67 years old)
ld)
Skin completely clear for many years; remains on strict diet
(no gluten, soy, refined carbs)
Physically active with no musculoskeletal complaints;
hands are pain-free despite doing lots of gardening

Objective

Heberdens nodes of 2nd & 3rd PIPs bilaterally;

No hot or boggy joints
Skin without inflammation or rashes
DEXA bone scan: osteopenia of lumbar spine (T: -1.7) and
femoral neck (T: -1.9): improved since 2005

Case #4
Chronic dermatitis & arthralgias
12 year follow-up (2010)
Ongoing regimen:

Fish oil: 2 tsp qd = 2000 mg EPA + 1500 mg DHA

Vitamin D drops: 4000 IU qd (summer); 6000 IU qd (winter)
Vitamin K2 (MK4 liquid): 20 mg qd
Calcium: microcrystalline hydroxyapatite & citrate: 1200 mg
Magnesium: 400 mg
Glucosamine sulfate: 750 bid
Organic
O
ga c ssilica
ca (c
(choline-stabilized
o e s ab ed o
orthosilicic
os c c ac
acid):
d) 10
0 mg
g qd
Green tea powdered concentrate: 2 packets qd (=10 cups)
DHEA: 25 mg
Sulforaphane glucosinolate: 100 mg qd
Probiotic: 100 billion CFUs (mixture Lactobacilli & Bifidobacteria)

Dermatitis Herpetiformis
p
Chronic intensely pruritic papulovesicular eruption,
typically starts age 20-30 years
Less than 10% of people with DH have GI Sx
AD associated with gluten-sensitive enteropathy;
IgA deposition in skin + accumulation of
neutrophils
Autoantigen = epidermal transglutaminase (eTG)
Associated with autoimmune thyroiditis, SLE, RA,
IDDM, Sjgren's, vitiligo, sarcoid, myasthenia
gravis
Increased
I
d long-term
l
t
risk
i k off GI lymphoma,
l
h
thyroid
th
id
nodules & cancer
Dermatitis quickly responds to dapsone, which has
no effect on intestinal pathology
Case reports of DH triggered by potassium iodide &
numerous pharmaceuticals

Dermatitis Herpetiformis

Autoimmune Disease: Promising

T
Treatment
O
Options
i
Low dose naltrexone (4.5 mg hs)
Tranilast
Methoxyestrogen
Vitamin D
E
Essential
ti l Fatty
F tt acids
id (EPA/DHA;
(EPA/DHA GLA)
Probiotics
Triptolide (Thundergod Vine)
Phytochemicals: sulforaphane, DIM resveratrol;
fermented wheat germ
Cordyceps sinensis

Autoimmune Disease:
Key Points
Autoimmune diseases are overlapping phenomena
rather than distinct entities
Approaching ADs as a maladaptive process rather
than a consequence of bad genes opens the door to a
wide range of treatment strategies
Innate immunity plays a much larger role in AD than
previously appreciated
Tolerance to microbes plays a major role in
maintaining tolerance to self
In addition to defending against pathogens, the innate
immune system responds to environmental triggers,
including diet & toxins; this interaction occurs largely
on epithelial & mucosal surfaces