Grand Rounds: Guggenheim mother and daughter team speaking on autoimmune disease mechanisms and tx
Carla G, DO (mother), Alena G, ND (daughter)
general on autoimmune, RA, SLE
immunology review
nonspecific cells: NK's, macrophages, eat antigen and present
MHCI presents to CD8 killer T cells
MHCII present to CD4 helper T's
costimulation is like our system of government with checks and balances
Th17: IL 21, 17a, 17f, 22, (IL10)
iTreg: TGFbta, IL24, 10
Th1: IfN gamma, IL2, Ltalpha (IL10)
GATA-3/stat5: IL4, 5, 13, 25, amphiregulin, IL10
Treg make TGF beta and IL10
depletion = self antigens in DM1, MS, RA
without tregs we'd all be autoimmune
explains why ai dzs occur together
IPEX ?? some dz where you get all AI at same time and die fast
NFkappaB
prot complets that controls gene trascription
first responder to stress signals
chronically active in inflam dz incl IBD, RA, sepsis, gastritis, asthma
work with this for pts that are chronically inflamed
TLRs on APCs
found on epithelial barriers, esp in the gut, skin, lungs, where we meet world
contacts everything and decides whether to instigate inflam
four TLR3, 7, 8 and 9 implicated in AI response to our own dead cells
produce IFN alpha and beta, IL6, 12, and TNF alpha
recruit helper T's, activate B's-->ab's
lupus et all characterized by IFN-1 activation
mucosa and gi flora over 2000 species are continuousin in contact with TLRs
luminal bact products help
maintain homeostasis and reg tolerance and inflam by activating specific TLRs
Myd88, Mal, TRIF, TRAM after TLR activation
probiotics
bifido incr TGF beta (Th3)
lactobacillus rhamnosus and bifido combo incr IL10, 12, TGF
normal flora increases sIgA
stims TLRs that suppress inflam
food supply lacks probiotics
lost bact supply from dirt
veggies not fresh
not eating fermented
Th3 oral tolerance
suppresses Th1 and 2
THF beta is dominant cytokine
occurs in gut, lungs, mucus membranes
regs Treg cells
naturopathic tenet: support our barriers
sunshine and AI disease
MS and all others
SLE, RA, Becet's, polymyositis, dermatomyositis, systemic scleroderma
all assoc with vit d def
*vit D def incr IL17 and IFN gamm producing T cells
140,000IUs at baseline and again at 4 weeks assoc with sig incr Tregs in apparently heatlhy individuals
this immunomodulatory effect may underlie asso of D with AI dz
ai thought of as idiopathic
poor food
no sun
maybe not so idiopathic
gut
Tregs made here, TLR stim, stim of NFkappaB
major source of ongoing pathogenic infx (dysbiosis)-->AI dz
major source of exogenous estrogens and toxic exposures
NFkappaB
activated by: high glycemic foods, linoleic acid, corn oil, obesity
***turning down: short time fasting, fish oil (lowers TNFalpha), stigmasterol, andrographis paniculata, lactobaccilus rhamnosus, curcumin, green tea, rosemary, GSE, propolis, reseveratrol, ALA, selenium, NAC, vit D, butyrate (butter)
pizza as AI inducing food
gluten connection
cheese is sat fat
processed meat with nitrates that destroy epithelial cells
tomatoes with leaky gut = allergy
her real feeling about food allergies: if you're eating food you shouldn't be allergic to it
early in dz do food allergy testing, avoidance diets, not long term tx strategy
address vit d def and chronic gi inflam and gi flora
mom pipes up: explosion of understanding of immunology is astounding
new understanding, increasing radically, complexity yet untold
her undergrad was in dance so med school was a challenge
she asks that we forgive the allopaths for what they have done
considering how little was known only a short time ago
AI dz is preventable
once cascade is started, you can't just stop it at the end of the process
HORMONES
more AI in women 4:1
ESTROGEN
exerts strong AI effect
changes cytokine production
incr B cell prolif
inhib B cell death
incr IFNgamma production
changes T cell gene transcription
perpetuates process of AI
EST METABOLITES
estrones: 4 and 16 are the bad and ugly
2 is good
urine concentrations of 2-oh est 10x lower in pts with RA and SLE than in healthy controls
ration of 16/2 was 20xmore in RA and SLE
B and T cells both have est resceptors on memb and respond to E2 by incr IgG and IgM production
16 oh est appears to exacerbate Th2 response
TNFalpha, Il6, IL1 all incr in AI dz
all stim aromatase activity in periphery
-->promoting conversion of DHEA to est instead of androgens
aromatase inhibitors:
EXOGENOUS EST
can induce AI dz
xenobiotics disrupt tolerance so that AI B cells not deleted
plastics, cosmetics, BPA, pesticides
bpa incr B cell autoab production
MODULATING EST OVERLOAD
curcumin counteracts proliferative effect of E2, most studied in CA
high dose and IV available outside US
cruciferous veggies
berries with DIM and indole 3 carbinol
lignans (whole grains, *flax, myristica argentea)
resvertatrol (wind and grape seeds)
enterolactone (whole grains, legumes)
chrysin (passiflora)
soya-derived isoflavone genistein (but she doesn't recommend soy for AI dz)
hops
her fave: ground flax seeds, daily, also incr SHBG
*melatonin downregs production of aromatase, sleep important
epigenetics
melatonin production is influenced across generations
pineal gland shrank with use of electrical lights
consider melatonin supp
flavonoids, flax, grape seed oil
*moderation in alcohol dt it decr liver metab of est
red wine 1-2 glasses/week is good still, stronger effect than suppression of alcohol
gluten
assoc with celiac and most AI
PITUITARY HORMONES
prolactin (prl) elevated in male and female pts with SLE
est stims ant pit to make prl
prl thought to act like cytokine, stims IFNgamma
SLE pt with elevated prl has more active dz and needs more prednisone to control it
chaste tree (vitex) best to turn down prolactin via dopaminergic effects
dose 1-2K mg/day divided
high prot meals and tyrosine increases prolactin!!
ADRENAL
SLE pts have lower cort, DHEA, androstenedione mbdt decr prodo or incr downstream conversion
add predinise and cort, DHEA and androstenedione decr even more
pts really need adrenal support, she tries to find the right DHEA dose for anyone on prednisone
DHEA helps reverse pred effects: inhibs osteop, skin thinning
ADRENAL SUPPORT
use herbs cautiously: withania, ginseng, astraglus all drive Th1
safe to use: ribes nigrum, licorice
(she uses ribes for pts on steroids, they tolerate tapers better, less SE's of pred)
consider bovine adrenal and B5
routine/ritual, regular sleep and eat cycles
DHEA: CI in breast CA
must address stress-->incr sIgA-->incr tolerance-->decr AI process
RA remits during preg
mother has us stretch before sitting again. =D
twist of fate that she ended up in rheumatology
"these people didn't deserve it and I'm going to help them"
"Don't judge me too harshly; I use a lot of drugs"
her advice to pts: don't let kids eat sugar, eat real food
Michigan doesn't license naturopaths, does license acupx
RA
3:1 female
1% of pop
new dz, started in 1700's w sugar refining
not seen in ancient skeletons
psoriatic arthritis is seen in old skels
probably preventable, all tx is suboptimal
ARTIFICIAL SUGARS AS BAD?
artificial sugars may not citronlinate peptides in mouth
sugar's effect on dental ligaments and mouth infx is start of AI dz
"you set your mouth to sweet" with fake sugar-->more sugar consumption overall
fake sugar is "still evil"
molecular mimicry
RA and gingival infx
RA AI chraracterized by Ab response to citrullinated proteins
P. gingivalis citrullinates peptides in mouth-->subsequent generation of autoantigens that drive AI in RA represents possible causative linke btw gingivitis and RA
hypothesis of molecular mimicry in etio of RA, with citrullinated enolase as the specific antigen involved
smoking increases production of citrullinated proteins
CCPs = citrullinated peptides
RHEUMATOID FACTOR VS CCP AS MARKER FOR AI DZ
65% of hep c pts are RA factor positive
bacterial endocarditis even more RF+
CCP's are much more indicative of RA than RF
NEW RA DIAGNOSTIC CRITERIA: 6/10
CCP and RF (0-3)
# and siz of jts (0-5)
over 6 wks duration (1)
ESR and CRP elevated (1)
OLD CRITERIA: 4/7
morning stiffness lasting over 1 hour
3 simultaneous joints affected
hand involvement
symmetric arthritis
subcutaneous nodules (DDX: sarcoidosis, gout, lupus with indistinct histology
RF+ and or CCP+
radiographic changes
SED RATE
oldest known lab test
originally used to dx pregnancy
she thinks the lab is stupid
"If you can't tell the pt is sick, something is wrong with you".
metastatic cancer is the only thing you can find with a sed rate that you didn't already know
JOINTS INVOLVED IN RA
atlanto-axial
first thing that goes with RA in atlantoaxial joint: ability to turn head
50% of rot is in this joint, also get erosion of lig that holds dens
TMJs
crico-aretenoid-->gravelly voice in morning
shoulder, elbow, wrist, MCP, PIP
hip, knee, ankle, midfoot (few things affect this)
MTPS (often spares the first joint and hits the others)
NOT RA: DIPS except in very severe, SI, spine
RA
synovitis (can tell from edema)
periarticular osteopenia
joint space narrowing
bare area erosions (at edges of joint cartilage)-->ankylosis
subluxation
interosseous, thenar wasting
ulnar deviation of fingers (ulnar interosseous mm are stronger than radial)
(Martha Graham choreographer: pathology become art, hands taught to students are RA typical)
tendon rupture, contractures
carpal collapse
nodules
loss of fx
palindromic (good days, bad days)
EVALUATION
HX
PE incl MS exam
LABS: CCP, RF, CBC, comp panel, ESR, crp, possibly ANA, HLA B27
X-rays: affected joints
"I could practice rheumatology in Timbuktu; I don't need the labs or x-rays"
ALLO TX
Corticoseroids (starts with 10-15mg and weans as fast as possible) and DMARDS:
Methotrexate, antifolate drug may inhib phosphorylation of acar to facar, given once a week, (given daily causes liver failure), folate daily to prevent mouth sores, increases cell turnover and causes birth defects (men and women stay off 4 mo before attempting conception)
(she now thinks of it as a homeopathic, low doses for RA used over 40 years)
(when she was a fellow they did liver bx after each 2gm dose, didn't allow pts to have any alcohol, now 2 drinks/day, 1/hour, 4/week but not with methotrexate)
(pt who took 2-4 beers/day for years, liver enzymes 3x elevated chronically, bx of liver reveals chronic changes, he lost his insurance, "we now live in a third world country", moved into a trailer, stopped coming to doc)
Plaquenil: antimalarial, not sure how it works, not a very good drug, few controlled with this alone, pts presenting with remitting RS3PE (pitting edema) variant do well on it, remitting variant hard to dx
Sulfasalazine (pt with AS almost completely fused at young age, wife wanted to get preg, sulfasalazine causes oligospermia)
Arava (just came out with black box warning re: fatal liver damage) interferes with 2nd Tcell signal, 100mg x3days then down to 20mg/day old dosing, causes diarrhea and pain, hair falls out. Was relatively cheap. Teratogen. Woman of childbearing age decides to get preg give cholestyramine x10 days and she will spend that time on the toilet, this gets it out of system. Metabolites have long halflife.
TNF agents. Interfere with TNF. Injectable, five on market: remicade (infusable monoclonal antibody from mouse, doesn't work after you have abs to it, very expensive, correl with disseminated histoplasmosis? perhaps, long t1/2, infuse at weeks 0, 2, 4, then every 5-8 weeks, costs $550/500mg dose, each infusion is $4-5K, she won't give it to anyone with animal contacts, birds esp, these people can get overwhelming infections) (she jumped on enbril and glad of it, it's the only soluble tnf drug, comes in 25 and 50mg doses, 25 in powdered form then dilute it so you can cut it in half, she'd taper them to 6.5mg/wk, less sting) (synzia is pegylated so you take it once a month, she will never prescribe it)
IL1 (anti-IL1 drug) out 7-8 years, she jumped on it, given daily, doesn't work. Still on market. Kinaret. reps say give it twice a day.
IL6 (brand new) Ticuzamab. "It will be a cold day in hell..." that day came. She has one pt on it, refractory to all else, horrible dz, doesn't seem to be working, 4th infus today.
Rituxan used for CA, goes after B cells and wipes them out. Good thing that IG has long t1/2. cold day in hell came for this one too. She has 5-6 pts on it. Reserved it for suicidal pts. Costs $20-30K/a pop, infused IV, insurance covers things given IV. Self injx not often covered. Suicidal pt doing well on it.
OT and PT
stabilizing and reconstructive surgery prn
LUPUS delivered in a big rush
10:1 FEMALE
11 CRITeria
worst in Afric
HX: seize, halluc, hair fall out, fluid heart and lung, pleuritic pain, lots more
ANA, DSDNA, C3, CR, ENA, CBC, COMP, DHEA, URINE, ACA, LA
steroids, plaq, methotrex, cellcept, cytoxin (lots of teratogens, carcinogens)
cytoxin causes infert in women, reserved for pts who are otherwise going to die
she's seen some deaths
runny rash on proximal digits