Respiratory Exam in 80hrs shit

RA Clinical

Physical changes to the joint space (3)

BPH

1. Pannus formation

2. Bone erosion (metalloproteinases degrading the matrix and Osteoclasts)

3. Hyperplasia (Fibroblasts)

Cells involved in RA

Th1 cells! (Not His related=> not Th2—>IgE—-> IL-4)

MTX MOA

1. Folate Synthesis

2. Adenosine

3. Polyamine (Spermine and Spermidine)

4. CK profile alteration

5. Adhesin (VCAM-1)

6. ROS (reduce T cell numbers)

Folate Metabolism

Folate—> Dihydrofolate —> Tetrahydrofolate—> dUMP—> dTMP

first two steps cat by dihydrofolate reductase

fx of THF

Methyl Donor

Adenosine Pathway Intracellular

MTX—-| AICAR Transformylase

AICAR build up inside the cell

AICAR—-| Adenosine deaminase

Adenosine enters the extracellular space via ENT1 transporters

Adenosine acts as a signalling molecule by binding to a GPCR A2A receptor

M1—> M2

CK decrease

TCR inhibition

Overdose of MTX

Leucovorin

What enzyme needs Me donor THF

thymidylate synthetase

Exraceullar Adenosine Pathway

ATP—>ADP—AMP—>A—> I

transmembrane CD39 ×2 (multiple by 2 steps get seventy something)

transmembrane CD73

Polyamine examples

Spermine and Spermidine are v. high in RA

Polyamine Pathway

Dihydrofolate Reductase inhibition leads to lowered number of THF which acts as a Methyl donor not only for dUMP but also METHIONINE AND S-ADENOSYLMETHIONINE

Action of ROS

increased apoptosis of T cells (Th1 cells mediate RA)

Which Adhesion molecules are affected

VCAM

ICAM-1

Leukocyte adhesion: ICAM-1 is expressed on endothelial cells (which line blood vessels) and binds to integrins (like LFA-1) on leukocytes.

Which pro-inf CK are affected by MTX

• IL-4

• IL-3

• TNF

• INFy

Effects of Sulfasalazine

—-| LOX 5-amino-salicyclic acid

—-|COX 5-amino-salicyclic acid

—-| NFKB ((nuclear factor kappa-light-chain-enhancer of activated B cells upregulates the expression of pro-inflammatory cytokines like TNF-α)

—- decreases O * made by neutrophils (radicals have no chanrge us)

—-| T and B cell proliferation

Sulfasalazine s/e

• Photosensitivity

• Myelosupression

• Hypoglycaemia in DM

• Orange discoluration of lenses and bodily fluids

• Thromboyctopenia

• GIT issues

• Tinnitus

Gold Compound Example

Au-thio-glucose

Au MOA

Phagocytosed by macrophages which decreases antigen processing

—-| NFKB as well

Au s/e

Priutus

Nephtotoxic (fat fed macrophages block tubules)

Ulcerations of the mouth

Leflomide MOA

decreased pyridine synthesis

Pencillamine MOA

Decreases the response in IL-1 (1st antibiotic)

Role of TNF-a

• chemokine production

• prostaglandin production

• neutrophil activation

• B cell activation

• pro-inflammatory cytokines (e.g. IL-1, IL-6)

• upregulates adhesion molecules like ICAM-1

• TNF-α promotes synovial fibroblast proliferation, matrix metalloproteinase

Two types of TNFa and two receptors

TNFa: membrane bound and soluble

TNFAR: 1 in all cells 2 in immune cells

TNFaR2 role

Survival of Tcells

Etanercept

Fc of IgG1

p75 tnfa receptor that binds both TNF alpha and beta (beta=its special power)

Infliximab

IgG1- antiTNF a a/b

will bind soluble and membrane bound TNF a

Adalimumab

anti-TNF antibody

s/e of using TNFa inhibitors

1. Immunosupression (malignancy/ invasive infection/ opportunistic pathogens)

2. Heart Failure

3. Congenital Abnormalities

4. Lupus-like disease

5. Infusion reactions

Anakinra

(IL-1R) antagonist that inhibits the binding of both IL-1α and IL-1β to the IL-1R

Juvenille

also used for gout along with canaki and rilonacept

Tocilizumab

binds the membrane bound and soluble IL-6 RECEPTOR

Abatacept

CD28 competition —> no full T cell activation

Rituximab

Anti-CD20 on B cells

Needs a MTX Rx

TNF used preferentially though

Ocelizumab

anti CD20 mab

(CD-20 B cell antigen) • Flags the B cells for destruction by body’s own immune system

Signs of RA

Tiredness/ more than 3 joints/ fever/ deformation of the joint/ anaemia/ loss of appetite

→ very much systemic effect!!

DX of RA

• Squeeze test

• Tender along joint line

• Synovitis

• +3 affected

  • Rheumatoid Factor (every immune disease has its bloodmarker!)

When to start a DMARD

3/12 of symptoms => then start ASAP

Why bridging therapy is needed?

Onset of action can be three months!!

When to taper CS

• repeated courses

• short course after a long course

• nocte

• 3 weeks

  • more than 7 days of 40mg

What is first line

MTX and Leflumide/ Sulphasalazine/Hydroxylchlorquine

• we want a combination!

Monitoring needed for MTX

weekly—> monthly—→ quaterly

eGFR (Clrenal) LFT and full blood count (due to myelosupression!!!)

Tests for Sulfasalazine

Well kind of none because you take it with MTX as first line and both require the same tests of LFT /GFR/ FBC every month/ quarterly when stabilised

Hydroxychloroquine caution

ocular toxicity (annual and pretreatment exam)

DDI with hydroxylcholoroquine

Antaacids!

s/e of Hydrochloroquine

Malaria—> mosquito bites—> rash

Etanocept:

TNFa 25mg twice weekly

TNFb 50mg once weekly

Rituximab dosing

2 infusions given that are two weeks apart (CD20)

Can be repeated 6 months later

Abatacept

Loading dose of an Infusion every 2 weeks three times

Then once monthly IV

or

Once weekly SC

Tests to be done before immunusupressants

Tuberculin skin test and X-ray for latent TB

When are biologics contraindicated

NYHA III

Before surgery

Baby making (congenital defects especially heart) O

OA

Primary and Seconcary Arth

1*= idiopathic

2+= trauma/ congenital disease/iflammatory

Risks

• high bmi

• female

• sport

• occupation

• trauma

• family hx

Why do a blood test

to exlude RA (rheumatoid factor)

Physical presentation

Heberden’s Nodes

Worsens with activity

Piroxicam

CAMERA DOWN YOUR MOUTH CUZ YA GOT ULCERS

Ketoprofen s/e

photosensitivity

Naproxen

least side effectsD

Diclofenac

CV event risk increased but more potent than ibuprofen

What is stronger than diclofenac

indomethacin

stronger=forteit mucosa as you burn holes in it

NSAID s/e

hyperkaelmia

ulceration

thromobosis

oedema —>HF decomp

renal insufficiency

Who is more predisposed to NSAID induced athma

female

middle age

chromic congestion

polyps

What are the NSAID Stopp Criteria (10 of them, think renal, heart, GIT)

1. with warfarin or a DOAC

2. antiplatelet w/o PPI

3. history or predisposition of PUD or GIT bleeds unless with concurrent PPI or H2-receptor

4. concurrent corticosteroids without PPI

5. older people

6. eGFR less than 50 mL

7. hypertension or severe heart failure

8. longer than 3 months symptom relief of osteoarthritis pain where paracetamol has not been tried

9. for chronic treatment of gout where there is no contraindication to a xanthine-oxidase inhibitor •

10. COX-2 selective NSAID in concurrent cardiovascular disease - increased risk of myocardial infarction and stroke

SSRI risk

increase bleeding risk

NSAIDs and MTX

Renal Insuffiency——extrapolate—— MTX clearance

Paracetamol in OA

4g/24 hrs max

change dose in hepatic impairment

Desperate Attempts at making it better:

Glucosamine

Chondrioitin

Intra-art inf once weekly for 5 weeks (help for about 2 weeks but invasive)

Joint replacent if you promise to DOAC :)

Keratin

Strong fibrous protein that keeps keratinocytes from getting destroyed

Epidermis cells:

• Melanocytes

• Langerhans cells

• Dead keratinocytes on top

Fx of skin

• acidic pH protection

• adipocytes in hypodermis for protection

• excretion

• D3

• nerves

• blood reservoir in the dermis

• social and sexual signalling

Fitzpatrick Skin Scale

type I —> risk of skin cancer, never tans

Type VI —> rare skin cancers and less sensitivive

Two melanins

Eumelanin (black)

Pheomelanin

How is eumelanin produced

Melanocyte-stimulating hormone stimulates the melanoCORTIN TYPE 1 RECEPTOR

increases cAMP levels and PKA is activated

UVC rays

shortest but filtered out by the ozone (100-290)

Effect of UVA

AGING

some reaches the epidermis

UVA= ROS

ROS damage DNA

decreaces Cells of Langerhans and APC (immunosupression= psoriasis and carcinogensis)

increases dermal inflammatory cells

Chromophores in cells

Melanin

Cellular DNA

Aromatic AA

= these absorb ultraviolet light

Effect of UVB

• some reaches the upper dermis

• direct DNA damage PYRIMIDINE DIMERS FORM)

  • stimulates vitamin D

What is PUVA

• PUVA (psoralen and UVA)

Inorganic Suncreen

TiO2 scatters UV light (some UVA as well)

Range of Protection 290-350 (some UVA as well clearly)

Chemical UV filters

Ethyl hexyl salicytate 2(6)asp

Absorb UV

Emit IR

Atopic Eczema Treatments

• Severe (cyclosporine, dupilumab: atopic dermatitis (eczema) and severe asthma. It works by blocking the IL-4 and IL-13 mycophenolate mofetil)

• Moderate (topical tacrolimus)

• Mild (topical calcineurin inh)

• Baseline (emollients)

Topical Calcineurin inh

Pimecrolimus

Tacrolimus

acrolimus ointment (Protopic® 0.03% and 0.1%) and pimecrolimus

When to use topical vs systemic

Topical: mild to moderate when CS not recommended, low systemic absorption

Systemic: rescue therapy, metabolism by CYP3A4

Lipophillic= long t/12

Side effects of Calcineurin INH

• alcohol intolerance

• infections

• discolaration

• papilloma:benign, non-cancerous tumor that grows on an epithelial surface

• premature delivery (lipophillic=> crosses the barrier)

• hyperkalaemia

Calcineurin INH MOA

Systemic ❤ Cyclophillin

Topical ❤ FKBP12 (isomerases)

• Drug–FKBP-12 complex forms inside T cells.

• This complex inhibits calcineurin, a calcium/calmodulin-dependent phosphatase.

• As a result, NFAT (nuclear factor of activated T-cells) stays phosphorylated and cannot enter the nucleus.

• Cytokine gene transcription (e.g. IL-2) is blocked → reduced T-cell activation and inflammation

Usual pathway for Il-2/3/4/tnf a transcription

APC presents an antigen via MHC to a TCR

Increase in Ca++

Activation of Calmodulin

Calmodulin activates Calcineurin

Calcinuerin dephosphorylates NFATc

NFAT enters the nucleus

Trans

What is Mycophenolate Mofetil used for

1. Lupus erythematosus

2. Pyoderma Gangrenosum

3. Severe Atopic Dermatitis

Mycophenolate Mofetil Activation

Esterases cleave it to mycophenolic acid M

ALL THESE QUESTIONS ARE FOR ATOPIC DERMATISIIS AND NOT PSORIASIS YET

MOA of Mycophenolic Acid

—-| inosine monophosphatase dehydrogeanse

less GMP avaible for T and B cell proliferation

Type I and Type II IMPDH

inosine monophosphatase dehydrogenase type II found in activated B and T cells

s/e of Mycophenolate Mofetil

• sepsis

• leucopenia

• infections

• malignancies

Dupilumab

Binds to IL-4R at the alpha subunit

(used for asthma and atopic derm both are TH2 mediated and IL-4)

IL-4 involved in a feedback loop that generates IL-13 and IL-4

DECREASES activation eosinphilcs and mast cells and basophils and B cell and T cells S

s/e of Dupilumab

• Eye inflammation

• Eye itchiness

• Herpes

• Vasculitis

  CUM IN UR EYES

Pathophysiology of Psoriasis

• epidermal hyperproliferation :differentiation of cells through the epider mis normally takes approximately 40 days, but in psoriatic skin may be as rapid as 7 days

• increased epidermal turnover

• thickened upper horny layer (hyperkeratosis)

• increased DNA synth

• keratin 6 and 16 increased

• keratin 1 and 10 delayed

• neutrophils in the epidermis

• CD8+ cells in the dermis

• f TH1- and TH17-mediated immune responses

• (TNF-α), interleukin (IL)-23 and IL-17

MOA of Glucocorticosteroids

• bind to glucocorticoids receptor complex

• release of chaperones

• dimerisation

• nucleus translocation

• bidning to glucorticoids response elements

• transcription of genes

Vitamin D use

1. reduction in keratinocyte proliferation

2. induces keratinocyte differentiation

3. immunomodulator function

What is combination therapy in Psoriasis

Calcipotriol acts on keratinocytes Vit D receptors

→ less IL-36-a and IL-36 y expressed

CS supress IL-17 (made by TH17 cells ) and IL-23 (made by dendritic cells)

IL-36aIL-36y and IL-17 and IL-23 are in a positive feedback loop

SYNERGISM BABY

Phototherapy in Psoriasis

PUVA = psoralen acts as a chromophore

Alone= chromophores in the skin absorb UV

When is Psoralne given

2 hours before UVA

Interactions with Psoralen

ACDH

FPNTT

Effect of PUVA

Type I reaction: O2 independent addition of psoralens to pyrimidine bases of DNA.

Type II reactions involve the transfer of energy to O2, creating a ROS.

Both reactions stimulate melanocytes and induce anti-proliferative, immune suppressive and anti-inflammatory effects.

Risk of interaction with photosensitizing meds: phenothiazines, thiazides, sulfonamides, NSAIDS, sulfonylureas, tetracyclines, and benzodiazepines