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Management of Autoimmune &utoinflammatory Disease:

Case StudiesDampening the Fire….

Robert Rountree, M.D.

Advanced Practice Module:Advanced Practice Module:The Many Faces of Immune Dysregulation andThe Many Faces of Immune Dysregulation and

Chronic InflammationChronic InflammationSanta Monica, CA

October 2010


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ec ves

• Explain the role that geneticsuscep y oes, an oes no , p ayin the development of autoimmunity

• Analyze case-based treatment

protocols for the management ofautoimmune diseases• Understand the roles that innate

mmun y, o erance o m cro es, anenvironmental triggers including diet &toxins play in the management of.


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“Horror Autotoxicus”Immune reactivity against se

• 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 long unchallenged despite counterevidence (e.g., lupus autoantibodies; AI hemolytic

anemia)• Autoimmunit eventuall acknowled ed in 1940-50’sas cause of many chronic diseases


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Autoimmune Disease:

• Self-directed tissue inflammation, resulting from

cell responses with development ofimmune reactivity towards native antigens

• Adaptive immune response (antibodies, activated

T lymphocytes) appears to play predominant rolein clinical disease, although innate immunity maybe the ultimate driver

• a op ys o ogy s ongo ng mu ac or a :organ or tissue-specific antibodies may predateclinical disease by many years

PLoS Med, 2006, Vol 3(8): 1242-1248


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Weaknesses of Autoimmune Disease =“ ”

• Self / nonself discrimination appearslacking for cancers• Most individuals harbor autoreactive

ymp ocy es w ou any s gn oautoimmune disease

associations found for many A.D.sPLoS Med, 2006, Vol 3(8): 1242-1248


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Innate Immune Mechanisms That Contribute to Autoimmune Disorders

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


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genes that predispose them to

.only a fraction of them go on to

eve op u - own au o mmunedisorders. Other mitigating factorstr ggers me ators must e

involved…


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“Mild forms of the autoimmune response probablyoccur naturally in most people. But, for people with apre spos on o au o mmun y, env ronmen afactors, 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


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utoimmune Disease: DelayedGratification

• any au o mmune seases o no eve opspontaneously, but instead evolve through anextended germination period before they become

…• 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 theprocess over time .


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Case #1

swelling; vomiting and diarrhea

• 35 year old female of Armenian descent• 14 yr. Hx of above Sx, recently in frequency,• Assoc. with low rade fever acute mildl WBC.

• Episodes consistently triggered by emotional stress.• Peritoneal tap during one of the episodes revealed

an abundance of neutrophils, but was sterile.• Episodes had ’d after Rx with daily colchicine

+ low dose amitriptyline (25 mg/d).• Symptoms helped with ondansetron &/ordicyclomine


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

• Working diagnosis =“Familial Mediterranean Fever”a a re aps ng po yseros s

• However,enetic testin UCLA FMF Clinic was ne ative

• Alternative diagnoses?

– recurrent angioedema – – nonspecific connective tissue disorder?


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Patient with recurrent abd. pain, migrainesSingle Nucleotide Polymorphisms


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Case #1R ecurrent episodes of severe abdominal pain &swelling; vomiting and diarrhea

• Initial interventions: – - – 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 infrequency and severity, energy , “It’s amazing.”

• Follow-up (@ 4 years): – on similar therapeutic regimen, including 75-100 mg DHEA

– still has episodic abdominal pain & migraines but severity & frequency muchreduced notes that salt and fat alleviate s m toms

– stress is most consistent trigger


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Case #1 en ear o ow-up

• “Much better overall.” No major attacks of abd pain in several

years, occ’l mild “flares” with marked fatigue, diffuse muscle/joint- , , -- -triggered by stress

• Meds & supplements – Colchicine, 0.6 mg tid – u oxet ne: mg: e n te y e ps sta ze moo , ecreases anx ety

– 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 – – Vitamin D3: 5000 IU – Probiotic: 100 CFUs qd

– L-glutamine: 5 grams qd – Oral bovine immuno lobulin concentrate: 5 rams – Lumbricus extract (with Atractyloides, Poria, Grass-Leaf Sweetflag root),

3 caps bid: “definitely helps with GI symptoms)


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Familial Mediterranean Fever

• One of several hereditar eriodic fever s ndromes• 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.

• Am loidosis is main com lication roteinuria . • 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, Vol345(24): 1748-1757


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Familial Mediterranean Fever

• Pathophysiology: neutrophil mediated

• Defect in MEFV gene results in defectivepyrin, a protein found in serosalneu rop s a eac va es c emo ac cfactors elicited by inflammatory stimuli

• Can overlap or co-exist with autoimmunediseases (Hashimoto’s, Polyarteritisnodosa)


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utoinflammation

• Self-directed inflammation, whereblocal factors (e.g., upregulatedcytokine signaling pathways) result

(DCs, macrophages, neutrophils),causing target tissue damage

• This is independent of adaptive

immune responsesPLoS Med, 2006, Vol 3(8): 1242-1248


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PLoS Med, 2006,Vol 3(8): 1242PLoS Med, 2006,Vol 3(8): 1242- -12481248


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Case #2

• Eval by D.C.: elevated lactulose/mannitolexcretion, low urinary testosterone, elevated

• Rx’d fish oil, testosterone/progesterone cream:little effect but sx gradually improved over 2years

• Current ROS: – mouth slightly better but still dry – eyes much better – – severe, chronic constipation; recent episode of diverticulitis

(taking antibiotics) – Low libido, "very moody” with anxiety & panic attacks, “I

don’t trust m bod an more” • Diet: mostly Paleo, organic, some grains, little

junk


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Case #2 ys ca xam

• : sc era con unc va mo s , no n ame• Neck: with parotid enlargement• Abd: al able stool in LU /LL

• MS: all joints FROM without tenderness;none boggy or hot

• • Skin: no rashes


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Case #2a s

• CBC: WNL Chem-screen: WNL• CRP: 3.0mg/L• ANA screen: 0.47 units; Neg anti-CCP• eg gren s au oan o es

(SS-A/Ro, SS-B/La)• SPEP: normal distribution• Food sensitivity panel (mediator release

test): multiple + foods (salmon & broccoli)


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Case #2x

• Bowel rest with functional food powder • : mg• GLA: 240 mg tid• Berberine: 200 tid• L-glutamine: 5-10 grams• Magnesium citrate: 200 mg tid• Psyllium husks, flax meal• Probiotics• St John’s Wort; Passionflower • DHEA: 25 m , testosterone cream: 2.5 m• Oligoantigenic diet (based on labs)


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Case #2 mont o ow-up

• Feeling much better: mouth not as dry--decreased need for gum; eyes OK, jointsOK (dancing regularly), libido improved onhormones; mood better after starting

paroxetine• Repeat DHEA-S: 21.2 mcg/dL• - • Free testosterone: 0.5 ng/dL (0.3-1.9)• E2: 71.29 pg/mL


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e s y o e

• One of most common ADs (after RA)• 3 million affected in US; 90% women;typical onset age 40 & older

•

& tissues• Biopsy is definitive -- antibody test

• Assoc with 44% increased risk oflymphoma


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The Influence of Sex Steroids onThe Influence of Sex Steroids on''

• “We believe that the driving factor behind Sjögren'ssyn rome cou e ac o an rogens. t as een s ownthat patients with Sjögren's syndrome have lowconcentrations of circulating dehydroepiandrosterone

- -

controls.• Our hypothesis is that patients with Sjögren's syndromesuffer from an insufficient local androgen effect in theexocrine target tissues of the disease because of lowsystemic levels and/or ineffective local intracrine handlingof DHEA-S prohormone”

Ann N Y Acad Sci. 2007 Jun;1108:426-32.


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Case #3:

• 36 year old white female

• swelling in hands/feet; found to have + RA titer, Rx’dwith NSAIDs, partial relief but Sx progressed toelbows/knees; had to curtail sports; worried abouts e e ec s o rugs

• Initial Rx: elemental diet fast (rice protein powder) for3 days, followed by modified elimination diet

• ar e , mg q , ax o , an ox an s,glucosamine, 1500 mg qd, MCHA, bromelain

(enzyme formula), ginger/curcumin/bioflavonoids“ ’ ” .


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Case #3: yo w t

• Lab: multiple +IgG foods; Rx’d oligoantigenicdiet; low animal fat, deep sea fish,nightshades

• . ,

1500 mg; GLA to 1200 mg• 2 month follow-up: 50% better, jogging &

walking again; Rx’d minocycline andprobiotics

,improved within 4 days of starting antibiotic


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Case #3: yo w t

• 7 month follow-up: “100% better”; only,

otherwise at full activity level; had tried stoppingeither minocycline or supplements butsymptoms recurred.

• 1 year later, retested IgG-food complexes andmodified diet accordingly, otherwise sameprogram.

• Follow-up two years after initial visit. Did well,then stopped minocycline for several months.

Had one flare and restarted, better within two.

supplements “permanently.”


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Symmetric Synovitis in Early Rheumatoid Arthritis


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Conventional Management of Rheumatoid Arthritis


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Initial Evaluation of the Patient with Polyarthritis


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Case #4 ron c ermat t s art ra g as

• HPI: 55 yo Hispanic woman in stable health until June, 1998, when she, ,

rash, starting on her hands then spreading to her neck, elbows andbuttocks. She felt that the rash had started after a period of eating aparticularly liberal diet compared to her usual restrictions (based on

.

• Consulted with a dermatologist, who prescribed a course of oralprednisone. Helped initially, but after tapering, symptoms recurred evenworse than before, with spreading to include larger area of arms, both

-, .performed which was read as "very suggestive” of dermatitisherpetiformis.

• Started on gluten-free diet plus numerous supplements (GLA, zinc, L-


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Case #4 ron c ermat t s art ra g as

• PMH: No prior history of rashes but occasional problems with.

• Hx of allergic rhinitis that improved after several years ofimmunotherapy. Long suspicious of food allergies, but couldnever confirm any specific correlations.

• ron c, recurren n ense rec a c ng or e pas - 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 orre . pprox ma e y en years pr or oo es s or ar r s, werereportedly negative.

• Also c/o recurrent neck pain, chronic right-sided sciatica andmuscle aches regularly treated with chiropractic manipulation formany years. MRI of the low back was reportedly normal.


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Case #4

Initial Labs• Intestinal permeability: Lactulose normal recovery at 0.3%,• mannitol depressed at 2%: elevated L/M ratio of 0.134• Celiac panel: Endomysial antibodies: normal (


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Case #4Chronic dermatitis & arthral iasClinical Course

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

, ,of which were excoriated and scaly.No hot, swollen or deformed joints

• Rx: Strict gluten-free diet, expanded to avoid corn, soy, dairy, yeast – – EPA-DHA: 1500 mg – Quercitin: 1 gm tid – Ginger extract: 2 caps daily – - – 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


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Case #4 Clinical Course

, ,manageable. Became aware that certain foods, especially soyproducts, could produce a reaction within two hours of ingestion. Themore 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 morechronic. Quercitin & ginger extracts seemed to alleviate the pain butnever eliminated it completely. The physical changes were subtle at

,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 allover, es eciall face.


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Case #4Chronic dermatitis & arthral ias

12 year follow-up (2010)

• u ec ve: ee grea years o – Skin completely clear for many years; remains on strict diet

(no gluten, soy, refined carbs) –

hands are “pain-free” despite doing lots of gardening

• – Heberden’s 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


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Case #4

12 year follow-up (2010)

• – 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 – Or anic silica choline-stabilized orthosilicic acid : 10 m d – Green tea powdered concentrate: 2 packets qd (=10 cups) – DHEA: 25 mg

– Sulforaphane glucosinolate: 100 mg qd –


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Dermatitis Her etiformis• 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 ofneutrophils

=

• Associated with autoimmune thyroiditis, SLE, RA,IDDM, Sjögren's, vitiligo, sarcoid, myastheniagravis

• ncrease ong-term r s o ymp oma, t yronodules & cancer

• Dermatitis quickly responds to dapsone, which has• Case reports of DH triggered by potassium iodide &

numerous pharmaceuticals


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Dermatitis Herpetiformis


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Autoimmune Disease: Promisingreatment pt ons

• Low dose naltrexone (4.5 mg hs)

• Methoxyestrogen• Vitamin D• ssen a a y ac s ;

• Probiotics• Triptolide (Thundergod Vine)• Phytochemicals: sulforaphane, DIM resveratrol;

fermented wheat germ

• Cordyceps sinensis


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Autoimmune Disease:Key Points

rather than distinct entities

• Approaching ADs as a maladaptive process ratherthan a consequence of bad genes opens the door to a

• Innate immunity plays a much larger role in AD thanpreviously 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 largelyon epithelial & mucosal surfaces

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