Drug treatments for Rheumatoid

Dr Steve JonesConsultant Rheumatologist

15 March 2012

Enzymes – chemical reactions cell metabolism

Examples: Methotrexate Non-steroidals

Drug action (1) – Enzyme blockers

Drug action (2) – cell signalling (e.g. hormones, growth factors, immune system)

Examples:

Positive signal - Signal blockers - Steroids Anti-TNFs Codeine

Drug effect depends on concentration …

… determined by balance intake & metabolism

Science Recap

Most drugs work by blocking enzymes (cell function/metabolism) or interfering with cell signalling (increase/decrease)

Drugs work best at specific concentration in body/tissues- Need for regular dosing - Differences in absorption/breakdown (genetics, disease)

affect ‘steady state’ concentration too low ineffective: too high side effects

Some drugs are “stored” in body tissues prolonged effect (Methotrexate - 1-2 weeks. Bisphosphonates (Alendronate etc) - weeks, months)

Analgesics“pain killers” - work on brain, not joints.

Paracetamol - max 4g daily (overdose liver damage)• safe but weak analgesic

Opiates - derivatives of Morphine (‘opium’)• naturally occurring system “endorphins” (pain/stress response)• act via receptors on nerve cells - pain system + others• including nerve cells controlling gut propulsion.

Opium poppies

Opiates – potency

weak medium strongDextropropoxyphene Dihydrocodeine Fentanyl

Codeine Tramadol MorphineBuprenorphine

Oxycodone

Depends on dose:

200mg Codeine = 100mg Tramadol = 10mg MST (Morphine)Max 1.2x Max 4x Max 20x (+)

Traditional : ‘Pain ladder’ – escalate between groups

But : M, K, D receptor types Codeine, Tramadol – M, Buprenorphine – Dm, Oxycodone – Km

overlap use in combinations

Opiates (3) Fixed combinations with Paracetamol• ALL MAX 8/d

Co-codamol (Codeine/Paracetamol) 8/500 (8mg Codeine, 500mg Paracetamol) - non-prescription15/500 (15mg Codeine)30/500 branded- Kapake, Solpadol, Tylex : identical

Co-dydramol (Dihydrocodeine/Paracetamol)7.6/500 - non-prescription 10/500 (usual) - equivalent to Cocodamol 15/500 20/500 “Remedeine” (equivalent to Kapake)

Tramacet (37.5mg Tramadol/325mg Paracetamol)

Opiate Combinations:

Plusses - easy to take

Minuses - possible Paracetamol overdose >8/d Inadequate analgesia (8,15,30?)

Inflexible dosing

In higher strengths (e.g. Cocodamol 30/500) : one tablet every 2-3 hours better than 2 every 4-6

Opiates (5) S/E:

• nausea, constipation – GI• drowsiness – brain• skin (nerves) – itching (antihistamines)

Constipation - worst with Codeine use softeners (eg lactulose) , and laxatives (senna)

‘Targinact’(Oxycodone + Naloxone) – expensive!

?addiction - rare - psychological “abuse”

high doses/long time - physical: “cold turkey” dependence ≠ addiction

Alternate delivery systems:

Patches - drug enters bloodstream through skin

Buprenorphine (BuTrans, Transtec) Fentanyl (Durogesic)

• less GI S/E• convenient (1, 2/week : variable doses)• occasional skin reactions, can fall off• relatively expensive

Sublingual – under tongue (Buprenorphine)Buccal – inside cheek (Fentanyl – cancer pain only)

rapid blood peak (often causes nausea)

Suppositories (Morphine)

NSAIDs (Non-Steroidal Anti-Inflammatory Drugs) - symptomatic treatment

Related chemically to Aspirin

Weak analgesic (= Paracetamol, low dose Codeine) – brain, jointsAntipyretic (fever) - brainAnti inflammatory – joints

• Use instead of / additional to Paracetamol, Opiates

NSAIDs work by :

Inhibiting COX enzyme (produces “prostaglandins”)- increase bloodflow and tissue fluid (inflammation)

=> swelling, heat & stiffness- sensitise pain nerves (inflammation)

BUT: COX also –

• needed for gastric mucus production “COX1”(dyspepsia, ulcers, stomach/bowel bleeding)

• needed for kidney blood flow regulation(hypertension, fluid retention, kidney impairment)

• involved in blood clotting (platelets)(heart attack & strokes)

NSAIDs (3)

“Standard”: Ibuprofen, Diclofenac, Naproxen, Indometacin

“COX2”: Meloxicam (?)‘coxibs’ Rofecoxib (Vioxx) - withdrawn (& others)

Etoricoxib - (Arcoxia)Celecoxib (Celebrex)

Coxibs “kinder on stomach” but: standard NSAID + Omeprazole cheaper routine - age > 60, history indigestion/ulcers

NSAIDs (4)

Benefits - additional pain relief, good for swelling/stiffness

Problems - Control symptoms of inflammation only, not process (exception- gout)

Anti-inflammatory potency = Side effect potency

Cardiovascular S/E –

Small increase heart attacks, strokes (controversial!)?Naproxen, lower doses safest Interfere with Aspirin for angina Aggravated by hypertension & fluid retention

Corticosteroids (“steroids”)

Prednisolone : Deflazocort : Dexamethasone

Mimic Cortisol (naturally occuring steroid hormone) • produced from adrenal glands

Basal - essential to health (= 1-2.5mg Prednisolone/d)(normal cell metabolism, blood pressure, salt balance)

Elevated stress response (infection, trauma..)Mobilises sugar + fat + protein reserves (repair)Anti-inflammatory. Anti-fatigue. Increases appetite.

Steroid Effects: Low doses (7.5mg or less) - Anti-inflammatory

(cell function and mobilisation)

Higher doses - ImmunosuppressantAnti-allergy

Uses: rheumatic diseases (RA, PMR, SLE…)inflammatory lung, liver, bowel, brain, muscle, skin disease

Benefits : control disease process, not just symptoms = ‘DMARD’ rapid onset action (24-48 hrs)

Steroids: Rheumatology Uses

- courses for flares or disease stabilisation with DMARD

Flares - usually only need 10-15mg Prednisolone daily(not 30mg given for COPD/asthma)

Injections - IM - (Kenalog, Depomedrone) - typically last 4 weeksIA - into joints (4-6 wks : need control disease as well)

Infusion (drip) - for severe flaresas part of immunusuppressive regime

(vasculitis, kidney disease)to reduce allergic side effects (Rituximab)

Steroid S/E (1):

“Cushings disease” - Excess Cortisol due to adrenal tumour

permanent “stress response”

• Weight gain (appetite and metabolism changes)• Thinning skin and bones/osteoporosis - muscle weakness - protein• Increased blood sugar (diabetes) and fats (cholesterol)• Insomnia and mood changes• Dyspepsia and peptic ulcers (NSAID-like)• High blood pressure, fluid retention

• Increased infections (higher doses)skin, chest, urine (immunosuppression)

Side effect risk = Dose x Time (patient sensitivity varies)

Steroid Side Effects (2):

“Addisons disease” - acute Cortisol deficiency(adrenal, pituitary gland damageLONG TERM STEROID USE)

• inability to mount stress response to trauma, infections• severe lethargy, fatigue, hypothermia• low blood pressure, low blood sugar/salt• severe cases cardiovascular collapse

DO NOT STOP STEROIDS SUDDENLY (“physical dependence”)- Carry Steroid card/alert bracelet- Only adjust steroid doses after medical advice- May need slow tail to stop (1mg/month reduction)- IV replacement (surgery)

All patients on regular steroids need: monitoring blood pressure, sugar and cholesterol screening and treatment for osteoporosis prevention? Omeprazole (PPI) for peptic ulcer prevention

& regular review to minimise steroid dose/stop if possible

Side effects unlikely from IA use (joint injections)- may get with repeated IM use

DMARDs “Disease modifiers”

Control underlying disease process. NOT CURE.Preventative - need taking regularly (even if disease inactive)

Effects - slow acting (disease inflammation symptoms) - reduce symptoms and signs inflammation - reduce/prevent longterm joint damage (disability) - reduce medical complications (including heart)

- reduce systemic upset (fever, anaemia, fatigue..)

DMARD Types:

1) Chemicals (‘small molecules’) : taken orally

Methotrexate, Azathioprine, Leflunomide, Cyclophosphamide“antimetabolites”

Block enzymes involved in cell growth/division main effects on actively dividing cells

• Immune cells (lymphocytes) - desired effect• Bone marrow (white blood cells, red cells)• Gut lining cells. Liver cells (metabolically active)• Cancer cells (chemo) • Foetus

Hence side effects -

GI upset (dyspepsia, nausea, mouth ulcers, diarrhoea)Blood problems (anaemia, low WCC, platelets)Liver inflammation (Methotrexate & alcohol also)

(Leflunomide &?InfectionsAvoid pregnancy (Azathioprine relatively safe)

Side effects worse with higher doses need slow dose escalation

Also problem with slow metabolisers:

Azathioprine - genetic test Methotrexate - kidney disease Allopurinol NSAID. Age

Leflunomide - excreted in bile and reabsorbed(drug persists even when stop taking)

Use - singly, work better in combination

Methotrexate and Leflunomide most effectiveMethotrexate best tolerated antimetabolite (+ Folic Acid)

Other DMARDs (weaker - different mechanisms)- Mild disease or drug combinations

• Sulfasalazine - salicylate and antibiotic (rash)• Gold & Penicillamine - kidney problems, rashes• Hydroxychloroquine – eye (rare)

Advantages – Oral Variable dosing

Relatively effective Infection rate similar Cheap (stop in severe)

Disadvanges - Slow onset action (weeks)GI side effecs common (?switch to injectable)Variation Methotrexate absorption‘Antimetabolite’ effect limited by S/E

● Incomplete control of severe cases ● Incomplete prevention of joint damage

Blood toxicity difficult to predict; rare cases fatal

DMARD types

2) Proteins : “Biologics”

Like insulin - produced by ‘genetic engineering’“brewed” - cell culture, not chemically synthesised intrinsically expensive to produce

All protein drugs digested by oral route (= “steak”)need giving parenterally (drip, subcut)

BIOLOGIC DRUG TARGETS

Types –

Anti-TNFs Infliximab(cell signal) Etanercept

AdalimumabCertolizumabGolimumab

Anti B cell (antibodies) RituximabAnti T cell (“helper”) AbataceptAnti IL6 (signal) Tocilizumab

* ALL SUPPRESS IMMUNE SYSTEM FUNCTIONS * (Infection risk!)

Biologics-

Advantages: more effective than conventional DMARDs(symptoms, joint protection)

Disadvantages:

cannot be used together (with other biologics)

increased common & rare infections (TB)Must stop drug during infection/surgery (flare risk)

? Patients with chronic infections(bronchiectasis, COPD, bone & joint, TB, hepatitis)

COST - rationing (“NICE guidelines”)

?? long term side effects BSRBR

Recap1:

Analgesics (Pain killers) “as required”Paracetamol, OpiatesWork on brain, not jointsWork best taken regularly (as all drugs) when neededCan use opiates in combination (eg. Butrans patch and Cocodamol)

NSAIDs (anti inflammatories ) “as required”Reduce pain, stiffness, swelling jointsNo effect on disease process/joint damageImprove quality of life/disability

Common side effects due to natural function of drug(GI/ulcers; hypertension - fluid; bleeding/clotting problems)Cannot mix with each other (avoid Nurofen/Ibuprofen and Naproxen)

Recap2:

DMARDs (including steroids) - “regular”Control disease process, secondary benefits swelling and painSlow acting. Can use in combinationVariably reduce joint damage, medical complicationsRegular monitoring essentialGradual dose increase reduces S/ESlow tail off steroids (don’t run out!)

Biologics: newer DMARDsGenetically engineered proteins (not oral)More effective, less side effectsUse limited by expenseNeed to stop during significant infectionsMay get “unusual” side effects (TB, MS) - but rare

Recap3: OTHERS

Coanalgesics (Amitriptyline, other antidepressants, Gabapentin etc)• Reduce “nerve pain”• Aid sleep (non-addictive)

Drugs for medical complications - (control cholesterol & blood pressure; prevent osteoporosis)

Supplements: Vit D/calciumFish oils?Glucosamine/Chondroitin?Iron deficiency common (NSAIDs)

SOME PRACTICAL ISSUES

Avoiding Side Effects : Minor

Is it due to drug?Common SE - Pharmacist/GP, ArthResUK leaflets, helplinePackage inserts - list all possible side effectsStatistical significance ≠ clinical(e.g. trial drug headache 15%, placebo 10% - only 1/3 HA due to drug)

Is it due to formulation/brand? “Excipients”

Could I get used to the drug? Reduce dose

If in doubt: stop drug few days then rechallenge

GI intolerance:

Take with food (absorption) InjectionsSlower dose increase PatchesSplit dose (Methotrexate, Sulfasalazine)Enteric coated/slow releaseAlcohol and tobacco …….

GI intolerance with multiple drugs:Marker of underlying problem Hiatus hernia, reflux, ulcers, Helicobacter, IBS?diet

Can I reduce dose?

Analgesics/NSAID - need may vary with time(flares/remissions/weather)Work quickly - no harm in temporary reduction

Consider non-drug methods:(rest, relaxation, hot/cold, rubs, splints, TENS ……)

DMARDs - ? lower dose combinations may reduce during remission, without flare

Avoiding major S/E

Illness, drug interactions & new medications(affect metabolism/drug levels)

Fever/chest infections - dehydrationUrine infections - transient reduction kidney functionAntibiotics - liver test problems, direct drug interactions

‘Red flags’• significant abdominal pain/jaundice• abnormal bruising or bleeding• serious or prolonged infection, high fever• unexplained breathlessness• protracted vomiting or diarrhoea• severe rash or oral ulceration

Avoiding major s/e 2

Immunosuppressants/biologics:

Immunisation status? (avoid live vaccines)Annual flu jabsAvoid contact with chickenpox/shinglesTropical disease risk (TB, Malaria…)

Biologics - stop during any infection/prior to operations (especially orthopaedic)

** Attend regularly for blood monitoring checks **

Why is my drug not working?

What are your expectations?DMARDs take weeks to work …….Steroids are poor painkillers …..Analgesics work better if taken regularly ……

Is it really not working?

Is the problem inflammation (stiffness, swelling) or pain (tenderness)?

Is the problem due to my Rheumatoid?Coexisting or secondary osteoarthritisBack pain – usually isn’tSoft tissue problems (tennis elbow, bursitis)

Why is my drug not working? 2

Are you taking enough (dose, route, genes, weight)?

Primary vs secondary failure?

DMARDs - rule of 1/3’s

Biologics “diminishing returns” 1st-3rd anti TNFHACA - Infliximab

NEW DEVELOPMENTS

1) Drug use

Minimise Inflammation x Time reduces damage

Early recognition RA and specialist treatmentObjective measure disease activity (DAS)Frequent regular follow-up (early or persistent disease)“Treat to target” - remission ideally

Use rapidly escalating dose of DMARD combinations - usually including Methotrexate

Temporary use steroids for rapid control (IM > oral)

Use minimum effective doses NSAID/anagesics - reduce s/e.

2) New Drugs

Chemicals ‘small molecule’ : tablets

- inhibitors of TNF production/metabolism (one effect of steroids…)

several under investigation (lab/animal study)

- lymphocyte activation blockers ‘JAK kinase inhibitor’ (Tofacitinib)

available EU/UK late 2012 (then NICE..)

‘Syk kinase inhibitor’ (Fostamatinib) works in RA but unacceptable S/E

2) New Drugs

Biologics

- other cell signal blockers (immunosuppressants)IL6 (Tocilizumab) – in useIL23 (Ustekinumab) – psoriasis ? Psoriatic arthritis (trials)IL17 (Secukinumab) – trials RA, PsA, ASIL18 – under development

* Potential problem – all similar to currently available drugs

- ‘Biosimilars’ (? cheaper, treat more people)Enbrel patent to 2028 : Humira to 2017

- Denosumab (biologic osteoporosis treatment) high doses reduce RA bone erosion/joint damage (preliminary, not yet licenced for RA…)

2) New Drugs

Cancer Biology (potential use in arthritis – yrs)

Abnormal cell growthNew blood vesselsConnective tissue damage (tumour invasion & spread)

e.g. experimental MMP’ase inhibitors (enzymes break down bone tumour spread, also RA erosions)

- Lung cancer trials

“Personalised medicine”?

Gene screening for - best drug to use (speed of effect, cost) - reduced risk of side effects

So far lots of research but no definite pointers(Rituximab - works better if seropositive- not absolute)

Clinical research? best use of existing drugs(current order of biologics use in UK determined mainly by cost …)