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

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

—- decreases O * made by neutrophils

—-| 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

Role of TNF-a

• chemokine production

• prostaglandin production

• neutrophil activation

• B cell activation

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

Anti IL-1

Juvenille

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

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:

25mg twice weekly

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 :)