Rheumatoid arthiritis Drug

Indomethacin MOA

Potent NSAID (INDOCID)

COX inh

CNS analgesic effect

Inhibits PNS motility (WBCs)

A/E of Indomethacin

Highly toxic (Take with food)

Dizzy

Vertigo

Headache

gastric irritation

constipation

Hydroxychloroquine MOA

Anitmalarial that also causes the remission of RA

Inhibits chemotaxis

Inhibits phospholipase A2 = Inhibition of proinflammatory cytokine (prostaglandins and leukotrienes) synthesis

Reduces IL-1 synthesis → message doesnt get out there

S/E - Hydroxychloroquine

RETINAL TOXICITY

QT prolongation → arrhythmia (C/I in drugs that have the same effect)

Blurred vision

headache

dizziness

Hydroxychloroquine use

early/mild RA use

Methotrexate dose

7.5-15mg per week (low dose)

Methotrexate MOA

dihydrofolate reductase inhibitor

Folic acid antagonist

Blocks dihydrofolate → tetrahydrofolate via thymidylate synthase

stops polyglutamate conjugates forming

Reduced 5 - lipoxygenase pathway- leucocytes

reduces IL-1 macrophages

S/E and toxicity of methotrexate

Adenosine regulates inflammation - receptor-mediated uptake of it is disturbed

Thrombocytopenia

Myelosuppression

Huge increase risk of cancers while on methotrexate

C/I methotrexate

NSAIDs (ONLY high doses of Methotrexate)

Probenecid

Sulfonamides

ALL ABOVE KEEP METHOTREXATE IN CIRCULATION FOR TOO LONG

Cyclosporin - accelerates - nephro and hepotoxicity (can be used together with dose adjustments)

antidote to methotrexate toxicity

Folinic acid (leucovorin) + divided doses over 24h if oral

Methotrexate benefit

Slows progression and less permanent damage to joints

Etanercept MOA

Fusion protien between 2 protiens: TNF receptor protien and Fc protien (that’s found on IgG).

Drug binds to TNF-a to block it from binding to the TNF receptors (the TNF resebling protien helps it do that).

Synviocytes, Osteoclasts and chondrocytes will hence won’t cause excessive inflammation (as TNF-a drives their work up).

Therefore, it blocks inflammation

Also binds to lymphotoxin-alpha, which also reduces inflammation, but not main machanism. (More relevant to treatment of juvenile arthiritis).

S/E of etanercept

Protien - hence it will cause:

• Swelling, pain, itching

Metastatic melanoma risks (its a TNF-a drug)

Allergic rxn

Immune response affected - vaccines may not work as well

Etanercept Dose

1-2 times a week

Low dose becuase it is potent

Infliximab MOA

Anti-TNF-a monoclonal

Similiar MOA to entanercept (except it is a monoclonal antibody)

A/E of infliximab

Infections and antichimeric antibody production

Domrant infections reactiviated!

Infusion site - eczema, erythmia, itching, pain, swelling

Vertigo

Serum sickness

Vomitting

Dizziness

Abdominal pain

fever

Infliximab dose

1 week plasma life therefore dose every 4-8 weeks

Combination with methotrexate (good 2 yr prognosis)

Adalimumab dose and benefit

2-week half-life

Fully humanised – reduced risk of anaphylaxis

Methotrexate combination - good

FYI used in psorasis and IBD

A/E adalimumab

Hyperlipideamia

Golimumab and Certolizumab pegol

G - 2 week half life

CP - rapid onset 2-4 wk dosing

Both work well with methotrexate (usually used with it due to increased synergy.

Why? stops antibodies from being formed by body to fight these drugs.)

Complaince is an issue (pain due to SC, a problem w all SC injections)

Anakira MOA

IL-receptor antagonist

Anakira Dose

100mg/day injection (SC)

2 weeks to see effect

Anakira A/E

Not humanised protien - injection site eyrythmia, ecchymosis, inflammation

headache

risk of serious infection

Neutropenia

C'/I Anakira

Anti-TNF-a drugs

Tocilizumab MOA

IL-6 targetting - most abundant IL in synovial joints of RA (& JIA) patients

Better given with methotrexate.

Tocilizumab Dose

IV dose once evry 4 wks (4mg/kg)

Tocilizumab A/E

possible increased AST and ALT levels (only while on drug)

Increased LDL levels, hypertension, headache and diziness

Nuetropenia

Janus Kinase Inhibitors MOA

Tofacitinib - Kinase 3, 1, 2 can be inhibted by this drug (in order of magnitude of inhibition, inhibits 3 the most)

Baricitinib - (1 and 2 kinase inhibition)

Upadacitinib (mostly Kinase 1 inhibition)

All prevent cell proliferation via JAK-STAT induction systems in the nucleus (that are supposed to produce cytokines)

Can induce apoptotic pathways in lymphocytes (tells the lymphocytes to perform programmed cell death).

Reduction of T-lymphoctyes (not just through cell programmed death?

C/I of JKIs

CYP3A4 and CYPC19 substrates (increases JKI serum levels)

Not TNF-a drugs

Haemoglobin <80g/L

A/E of JKIs

Latent infections may return

Increased cancer risk

Increased Lipid blood levels'

Reduced HR (Tofacitinib)

liver damage

aneamia

Gut perforations

Dose of JKIs

Tofacitinib - 5mg oral tabs bd

Baricitinib - 2-4mg d

Upadacitinib - 15mg d

Gold salts - general MOA

Gold builds in synovial joints (in reticuloendothelial cells like circulating macrophages)

Gold Salts - Aurothiomalate

Reduces the following:

Mitogen induced lymphocyte proliferation

release & activity of lysosomal enzymes

production of O2 radicals / metabolites

chemotaxis from neutrophils

mast cell mediator release

Gold salts - Auranofin MOA

Reduced induction of IL-1 and TNF-a

Gold salts A/E

Lesions in mucous membranes (grey/blue depositis)

Exfoliating dermatitis and other rashes (avoid if u have dermatitis alr)

peripheral neuropathy

Nephrotoxicity

• protienuria

Hepatitis

Encephalopathy

With Oral Auranofin:

• diarrhoea

• Stomatitis

• Nausea

• Vomiting

• Conjunctivitis

D-Penicillamine MOA

Reduced collagen formation , rheumatoid factor (marker of auto-immune disorder) and immune complex

Chelating ability - possible role

Cystiene substitue - makes soluble complexes with cystiene

D-Penicillamine - AEs C/I

Very similiar to gold

Allergic to penicillin - DO NOT USE (a metabolite of penicillin)

GI tract:

• Taste - everything tastes metallic

• Nasuea

• both these S/E can cause anorexia

Blood:

• Leukopenia - aplastic aneamia - STOP ASAP

• Autoimmune conditions

Rashes, stomatitis (stomach inflammation)

Protienuria

Goodpasture’s syndrome (not under gold’s AEs)

D-Penicillinamine dose

Start low with a gradual increase

Effectiveness: weeks to months

250mg daily for a month, and increases ~every month

Leflunomide MOA

Prodrug

Pyrimidine inhibitor (dihydroorotate dehydrogenase inhibitor)

Lymphocyte proliferation blocked

Reduces joint swelling

Dose of leflunomide

Starts 100mg/d — 3 days, then 5-25 mg/d

long half life → <2 weeks

C/I Leflunomide and antidote

Warfarin and phenytoin → CYP2C9 inhibition

Methotrexate - increases hepatoxicity (still can be used together w/ caution)

Preg - teratogenic - leave off getting pregnant up to 6 months after ur last dose.

B/F - will get in milk

Othe liver damaging drugs taken with leflunomide can cause liver failure

Cholestyramine - helps to eliminate drug faster if patient exposed to toxicity

AEs of Leflunomide

Hepatotoxicity

N, V, D

Hair loss

Weight loss

Weakness

Headache

‘Dizziness

Pnuenmonia

Peripheral nueropathy

Hypertension (Measure BP prior to treatment!)

SUMMARY OF RA DRUGS

Symptoms of RA to dientify in patients

Maise

Fatigue

SYMMETRICAL pattern of joint pain, stiffness, swelling and redness

Involvement of MCP, PIP & MTP joints (too long to list real names)

NOT usually the joints closest to your nails (that’s more osteoarthiritis)

Morning stiffness

Weight loss

Fever

Depression

Lab results to look for

elevated:

• Erythrocyte Sedimentation Rate (ESR)

• CRP

Presence of RF (an antibody present when body undergoing autoimmune diseases, detected less in early stages of RA)

HLA typing → looks for genetic markers in blood that are associated with RA

Antinuclear Antibody

Antibody to CCP (appears before symptoms appear)

Normocytic normochromic Aneamia: low serum iron, normal to low TIBC, and normal to high ferritin

Changes in joint radiographs

Non-drug interventions of RA

Mediterranean diet

Physio, exercise

Smoking cessation

Immunisation

Omega-3 fatty acid supplement (fish oil - 2.7g d)

Gamma linolenic acid (GLA) — evening primose oil (up to 2.8g GLA daily).

• reduces inflammatory cytokines

First line for RA

NSAIDs

COX-2 selective or non-selective inhibitors

Trail and error between different NSAIDs

lowest dose for shortest time

Can be used with paracetamol

Avoid w/ corticosteroids and anticoags - risk of GI bleeding

PPI prophylaxis in over 65s and patients w/ history of PUD

Peroxicam → highest risk of GI bleeding

Ibuprofen - lowest risk of GI bleeding

Second line for RA

Corticosteroids:

• Bridge therapy while waiting for DMARDs (like methotrexate to work)

• calms “disease flares”

• IM or IV

• Intraarticular injections with methylpredinisolone acetate 120mg → prolonged effect of 8 wks, not repeated in same joints > 4x per year

  • Followed by 24-48 hour splint and bed rest

  • Risk: infection, osteonecrosis, and tendon rupture

Corticosteroid dose

Prednisolone 5-15mg d

used at lowest possible dose for shortest time possible

if treatment is >3 wks ot patient on >7.5mg d, taper dose slowly to cease

Advantages and disadvantages of corticosteroid use

+
Reduces pain/swelling dramatically

Reduced disease progression

-

lower dose = lower efficacy

Undesirable S/Es w/ long term use (like dyspepsia and hyperglycemia)

Third line

DMARDs (there’s first line and second line under these)

Reduces synovial inflammation and prevent joint damage

Slow onset: 2-6 months

Combination therapy preferred (monotherapy usually not enough)

Should be introduced at the time diagnosis (ASAP)

Sulfasalazine - 1st line DMARD

1st line in mild disease

Dose 500mg daily → max: 1.5g

4-12 weeks for onset

G6PD and sulfonamide allergy – screen patient and avoid this drug if present

GI AEs minimised with EC tablet

Another AE: blood dycrasias

Monitor FBP, CrCl, LFTs

Hydroxychloroquine - 1st line DMARD

In mild disease - 1st line (less effective + less toxic)

Used in combination w/ other DMARDs

200mg - 400mg daily

onset - 2-6 months

G6PD deficiency – screen patient for it and avoid using drug if present

Retinopathy (endoapthamology reviews important), worsening posarisis

Monitor FBP, CrCl, LFT

Methotrexate - 1st line for moderate to severe RA

DMARD

most commonly used drug in RA patients

onset quick: 4-6 wks

Used alone/combination

Combos: Methotrexate + hydroxychloroquine/sulfasalazine/leflunomide

10- 25 mg WEEKLY!!! oral

Folic acid 5-10mg – coadministered to avoid GI toxicity and mouth ulcers

At least 24 hour gap between methotrexate and folic acid doses

ONLY high-dose methotrexate - interaction with NSAIDs

Monitor FBP, CrCl, LFTs, CXR

Leflunomide - 2nd line DMARD

Used if methotrexate is not suitable

onset - 4weeks

10-20mg d

Trasient elevation of AST & ALT

Monitor FBP, CrCl, LFTs, BP

3rd line - Biological DMARDs

Used when synthetic DMARDs didn’t work

Used with methotrexate usually

Don’t use >1 Biological DMARD → increased risk of infection and malignancy

Monitor for infection, especially latent ones (Hep B and TB in particular)

Pneumococcal, influenza, Hep A and B, and HPV vaccines are essential

Biological DMARDs - TNF-a Inhibiors

C/I in patients with TB, hepatitis B and C, grade III/IV heart failure

AEs (already mentioned): infusion/injection site reactions, URTIs and other infections, thrombocytopenia, malignancies

Monitor FBP, CrCl, LFT

Biological DMARDs - Rituximab

Severe RA not responding to TNF-α inhibitor

Onset: 4 months

Administered as IV infusion

A/Es: infusion related reactions, infections, muscle pain, weakness

Monitoring: FBP, LFT and CrCl

Biological DMARDs- Abatacept

Reserved for RA not responding to TNF-α inhibitor

Onset: 14 days

Administered by IV infusion

A/Es: Infusion related reactions, infections, hypertension, increased liver enzymes, blood dyscrasias, hypersensitivity

Monitoring: FBP, LFT and CrCl

Biological DMARDs - Anakinra

Slower onset (2 weeks)

less effective than TNF-α inhibitors

Administered by SC inj

A/Es: injection site reactions, neutropenia, serious infections, raised total cholesterol (monitor levels)

Monitoring: FBP and lipid profile

Biological DMARDs - Tocilizumab

Tocilizumab

Onset: 2-4 weeks

Administered by IV infusion

A/Es: infusion site reactions, neutropenia, thrombocytopenia, hyperlipidaemia, infections, GI ulceration

Monitoring: FBP, LFT, lipids

Biological DMARDs -Tofacitinib

Moderate to severe RA after failed methotrexate and TNF alpha antagonist treatment

Can be used as monotherapy or in combination with other DMARDs (except cyclosporine, azathioprine)

C/I: TB, hepatitis B and C

A/Es: Infections, elevated LFT, diarrhoea, nausea, rash, headache, dyslipidaemia, blood dyscrasias, GI perforation

Monitoring: FBC, Hb, lipid, LFT

Biological DMARDs - Baricitinib

Used in combination with Methotrexate

C/I: TB, hepatitis B and C

A/Es: Nausea, abdominal pain, infections, elevated CK and LFT, dyslipidaemia, blood dyscrasia

Monitoring: FBC, Hb, lipid, LFT

Summary of Treatment algoirthm

On slide 39 of last lecture

Measuring success of treatment

Number of tender and swollen joints

Duration of morning stiffness (<1 hour?)

ESR and CRP

Functional status

Monitor development of extra-articular manifestations → problems outside the joints (lungs, depression etc)